CN101977621A - Fluorinated tripeptide hcv serine protease inhibitors - Google Patents

Fluorinated tripeptide hcv serine protease inhibitors Download PDF

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CN101977621A
CN101977621A CN200880126009XA CN200880126009A CN101977621A CN 101977621 A CN101977621 A CN 101977621A CN 200880126009X A CN200880126009X A CN 200880126009XA CN 200880126009 A CN200880126009 A CN 200880126009A CN 101977621 A CN101977621 A CN 101977621A
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replacement
heteroaryl
aryl
cycloalkyl
chemical compound
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盖永华
柯日新
王喆
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Enanta Pharmaceuticals Inc
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Enanta Pharmaceuticals Inc
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Abstract

The present invention relates to compounds of Formula I, or a pharmaceutically acceptable salt, ester, or prodrug, thereof: ( I ) which inhibit serine protease activity, particularly the activity of hepatitis c virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis c virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Description

Fluoridize tripeptides HCV serpin
Related application
The rights and interests of the U.S. Provisional Application that the application requires that December in 2007 submitted on the 5th U.S. Provisional Application is submitted to number on January 24th, 60/992,574 and 2008 number 61/023,254.More than each the application content incorporate this paper by reference into.
Technical field
The present invention relates to fluoridize tripeptides, they have the antiviral activity of anti-HCV, and can be used for treating the HCV infection.More particularly, the present invention relates to novel tripeptide compound, the method that comprises this type of compound compositions, uses their method and prepare this compounds.
Background technology
HCV is the main cause of non-A non-B hepatitis, all is a serious day by day public health problem in developed country and developing country.Estimate that the whole world surpasses 200 million peoples and infects this virus, surpass almost 5 times of infected person immunodeficiency virus (HIV) number.Because the chronically infected individuality of suffering from of high percent arranged, the HCV infected patient form liver cirrhosis, subsequently develop into hepatocarcinoma and late period hepatopathy risk very high.In western countries, HCV is the common cause of hepatocarcinoma and needs of patients liver transplantation.
In the exploitation of anti-HCV therapy, there is considerable obstacle, includes but not limited to that persistence, the genetic diversity when virus is duplicated, the virus of virus form the high rate of drug resistance mutant, lack reproducible infection cultivating system and HCV duplicates and pathogenetic small animal model in the host.As a rule, in view of the infection of the gentle course of disease and the complex biological feature of liver, carefully whether consideration uses antiviral agents, because produce very big side effect probably.
The Therapeutic Method that has only two kinds of HCV to infect at present goes through to use.Original therapeutic scheme is usually directed to intravenous and gives interferon-' alpha ' (IFN-α) 3-12 month, and newly approved second filial generation therapy relates to IFN-α and conventional anti-viral nucleoside analogies (as ribavirin) therapeutic alliance.All there is the relevant side effect of interferon in these two kinds of treatments, and the effect that anti-HCV infects is low.Because existing therapy toleration difference and usefulness are disappointing, so be necessary to develop the effective antiviral that treatment HCV infects.
In patient crowd, most of individuality is chronic infection and asymptomatic, acatalepsia, and the side effect of active drug must significantly be less than the side effect of existing therapy.Hepatitis C non-structural protein-3 (NS3) is a kind of proteolytic enzyme, and it is that viral polyprotein of processing and the virus replication that causes thus are necessary.Although exist a large amount of HCV to infect relevant virus variation body, still highly preserve in NS3 proteinase activity site, makes its inhibitory action become a kind of attractive intervention pattern thus.Recently such viewpoint has been supported in the successful treatment of HIV: in anti-HCV, be a crucial target to the inhibition of NS3 with protease inhibitor.
HCV is a kind of flaviviridae (flaviridae) RNA viruses.The HCV genome is comprised the single stranded RNA molecule of being made up of about 9600 base pairs by peplos.Its coding is by about 3010 polypeptide that aminoacid is formed.
The HCV polyprotein is processed as 10 letter (discreet) peptides with difference in functionality by virus and host's peptidase.Three kinds of structural protein are arranged, C, E1 and E2.The proteic Unknown Function of P7 is made up of highly unstable sequence.6 kinds of non-structural proteins are arranged.NS2 is a kind of zinc dependency metalloproteases, works in bound fraction NS3 albumen.NS3 comprises two kinds of catalysiss (it and bonded NS2 are divided to be opened): the serine protease function of N-end, it needs cofactor NS4A, the ATP-ase-dependency helicase function of carboxyl terminal.NS4A is a kind of non-covalent cofactor of combining closely of serine protease.
NS3-NS4A protease participates in four sites of the viral polyprotein of cutting.The NS3-NS4A cracking is the cracking of autocatalysis type cis.Its excess-three kind hydrolyzing N S4A-NS4B, NS4B-NS5A and NS5A-NS5B are trans hydrolysis.NS3 is the serine protease that belongs to chymotrypsin-like proteinase on a kind of structure.Though the NS serine protease itself has proteolytic activity, with regard to the cracking of catalysis polyprotein, HCV protease is not a kind of effective enzyme.Verified, the proteic center of NS4A hydrophobic region is necessary for this potentiation.As if NS3 albumen and NS4A formation complex is that the processing incident is necessary, renders a service with the Proteolytic enzyme that strengthens all sites.
The exploitation antiviral drugs general strategy be enzyme (the comprising NS3) inactivation that makes encoding viral, and these enzymes virus replication is necessary just.S.Tan, A.Pause, Y.Shi, N.Sonenberg, Hepatitis C Therapeutics:Current Status and Emerging Strategies, NatureRev.Drug Discov., 1,867-881 (2002) has summed up the on going result of exploitation NS3 protease inhibitor.。
Summary of the invention
Summary of the invention
The method that the present invention relates to novel tripeptide compound and in the experimenter who has this treatment to need, treat hepatitis C infection with described tripeptide compound.The invention further relates to pharmaceutical composition, its comprise independent or with The compounds of this invention or the acceptable salt of its pharmacy, ester or the prodrug of pharmaceutically acceptable carrier or excipient composition.
In one embodiment of the invention, chemical compound shown in the formula I or the acceptable salt of its pharmacy, ester or prodrug are disclosed:
In one embodiment of the invention, formula I chemical compound is disclosed:
Figure BPA00001188361900031
And the acceptable salt of pharmacy, ester and prodrug, wherein:
M be do not exist, O, S, S (O), SO 2, NH, O (CO), NH (CO), NH (CO) NH, NHSO 2, NHSO 2The alkenylene of alkylidene, alkenylene or the replacement of NH, NH (CO) O, alkylidene, replacement;
Cy is selected from aryl, the heteroaryl of hydrogen, aryl, replacement; The cycloalkenyl group of the cycloalkyl of the heterocycle of the heteroaryl that replaces, heterocycle, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement and
Figure BPA00001188361900032
Wherein
R 1And R 2Be independently selected from:
A) hydrogen;
B) aryl;
C) aryl of Qu Daiing;
D) heteroaryl;
E) heteroaryl of Qu Daiing;
F) heterocycle of heterocycle or replacement;
G)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
H) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
I)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
J) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group;
K)-Q-R 3, wherein Q is (CO), (CO) O, (CO) NR 4, (SO), (SO 2), (SO 2) NR 4And R 3And R 4Be independently selected from:
(i) hydrogen;
(ii) aryl;
The (iii) aryl of Qu Daiing;
(iv) heteroaryl;
(the v) heteroaryl of Qu Daiing;
(vi) heterocycle;
(the vii) heterocycle of Qu Daiing;
(viii)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(ix) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(x)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
(xi) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group; Perhaps R 1And R 2The carbon atom that connects with their forms and is selected from following loop section: replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle; Perhaps replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle its comprise that with one or more following group condenses: the cycloalkenyl group of the cycloalkyl of the heterocycle of the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, heterocycle, replacement, cycloalkyl, replacement, cycloalkenyl group and replacement separately;
G is-E-R 3, wherein E does not exist or E is O, CO, (CO) O, (CO) NH, NR 5, NH (CO), NH (CO) NH, NH (SO 2) NH or NHSO 2
A is selected from R 5, (CO) R 5, (CO) OR 5, (CO) NHR 5, SO 2R 5, (SO 2) OR 5And SO 2NHR 5
R 5Be selected from:
A) hydrogen
B) aryl;
C) aryl of Qu Daiing;
D) heteroaryl;
E) heteroaryl of Qu Daiing;
F) heterocycle;
G) heterocycle of Qu Daiing;
H)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
I) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
J)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
K) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group;
B is H or CH 3
L is selected from:
(i) hydrogen;
(ii) aryl;
The (iii) aryl of Qu Daiing;
(iv) heteroaryl;
(the v) heteroaryl of Qu Daiing;
(vi) heterocycle;
(the vii) heterocycle of Qu Daiing;
(viii)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(ix) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(x)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
(xi) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group;
Z 1And Z 2Be independently selected from halogen; Preferred F, Cl and Br;
M=0,1,2 or 3;
N=1,2 or 3; With
H=1,2 or 3.
In another embodiment, the present invention is characterized as pharmaceutical composition, and it comprises The compounds of this invention or the acceptable salt of its pharmacy, ester or prodrug.In another embodiment more of the present invention, pharmaceutical composition is disclosed, it comprises The compounds of this invention or the acceptable salt of its pharmacy, ester or prodrug with the treatment effective dose of pharmaceutically acceptable carrier or excipient composition.In the present invention again in another embodiment, be in the experimenter of this treatment of needs with the method for described medicine composite for curing hepatitis C infection.
Detailed Description Of The Invention
First embodiment of the invention is chemical compound or the acceptable salt of its pharmacy, ester or the prodrug that formula I mentioned above represents, its separately or with pharmaceutically acceptable carrier or excipient composition.
Another embodiment of the present invention is a chemical compound shown in the formula II:
Or the acceptable salt of its pharmacy, ester or prodrug, its separately or with pharmaceutically acceptable carrier or excipient composition, wherein A, L, M, Cy, G, Z 1And Z 2Be that previous embodiments is defined.
Another embodiment of the present invention is a chemical compound shown in the formula III:
Figure BPA00001188361900062
Or the acceptable salt of its pharmacy, ester or prodrug, its separately or with pharmaceutically acceptable carrier or excipient composition; Wherein
R 6Be selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement; J be do not exist or be selected from-O-,-S-,-N (R 5)-,-C (O)-,-C (O) N (R 5)-,-C (O) O-,-N (R 5) C (O)-,-NH (CO) NH-,-N (R 5) SO 2-, alkylidene, alkenylene, alkynylene; R wherein 5Be that first embodiment is defined.
Each R 71, R 72, R 73And R 74Be independently selected from:
(i) hydrogen;
(ii) halogen;
(iii)-NO 2；
(iv)-CN；
(v)-M-R 4, wherein M does not exist, perhaps O, S, NH, N (R 5);
(vi) aryl;
(the vii) aryl of Qu Daiing;
(viii) heteroaryl;
(ix) heteroaryl of Qu Daiing;
(x) Heterocyclylalkyl; With
(xi) Heterocyclylalkyl of Qu Daiing;
Wherein A, L, G, Z 1, Z 2, R 4And R 5Be that aforementioned first embodiment is defined.
In one embodiment, A is selected from H, R 1,-(C=O)-O-R 1, R wherein 1Be selected from aryl; The aryl that replaces; Heteroaryl; The heteroaryl that replaces; The Heterocyclylalkyl of Heterocyclylalkyl or replacement;-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately; Replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl;-C 3-C 12Cycloalkenyl group or replacement-C 3-C 12Cycloalkenyl group.R 6Be selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement.J does not exist.G can be-NH-SO 2-NR 4R 5Or-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group, and R 4And R 5Be selected from independently of one another hydrogen ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8The heterocycle of the heteroaryl of the aryl of alkynyl, aryl, replacement, heteroaryl, replacement, heterocycle, replacement ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Each R 71, R 72, R 73And R 74Be independently selected from hydrogen, halogen ,-NO 2,-CN ,-M-R 4, wherein M does not exist, perhaps O, S, NH, N (R 5), the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl and the replacement of the aryl of aryl, replacement, heteroaryl, replacement.Z 1And Z 2Can be independently selected from F, Cl and Br.
In another embodiment again, A is selected from H, R 1, R wherein 1Be selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately; Replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl;-C 3-C 12Cycloalkenyl group or replacement-C 3-C 12Cycloalkenyl group.R 6Be selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement.J does not exist.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Each R 71, R 72, R 73And R 74Be independently selected from hydrogen, halogen ,-NO 2,-CN and-O-R 4, R wherein 4Be defined as just top embodiment.Z 1And Z 2Can be independently selected from F, Cl and Br.
Another embodiment of the present invention is a chemical compound shown in the formula IV:
Figure BPA00001188361900081
R wherein 6, R 71, R 72, R 73, R 74With J be that previous embodiments is defined; And A, L, G, Z 1And Z 2Be that aforementioned first embodiment is defined.
In one embodiment, A is selected from H, R 1,-(C=O)-O-R 1, R wherein 1Be selected from aryl; The aryl that replaces; Heteroaryl; The heteroaryl that replaces; The Heterocyclylalkyl of Heterocyclylalkyl or replacement;-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately; Replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl;-C 3-C 12Cycloalkenyl group or replacement-C 3-C 12Cycloalkenyl group.R 6Be selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement.J does not exist.G can be-NH-SO 2-NR 4R 5Or-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group, and R 4And R 5Be selected from independently of one another hydrogen ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8The heterocycle of the heteroaryl of the aryl of alkynyl, aryl, replacement, heteroaryl, replacement, heterocycle, replacement ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Each R 71, R 72, R 73And R 74Be independently selected from hydrogen, halogen ,-NO 2,-CN ,-M-R 4, wherein M does not exist, perhaps O, S, NH, NR 5, aryl, replacement the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl and replacement of aryl, heteroaryl, replacement, R wherein 4, R 5Be to define as described above.Z 1And Z 2Can be independently selected from F, Cl and Br.
In another embodiment again, A is selected from H, R 1, R wherein 1Be selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately; Replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl;-C 3-C 12Cycloalkenyl group or replacement-C 3-C 12Cycloalkenyl group.R 6Be selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement.J does not exist.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Each R 71, R 72, R 73And R 74Be independently selected from hydrogen, halogen ,-NO 2,-CN.Z 1And Z 2Can be independently selected from F, Cl and Br.
Another embodiment of the present invention is a chemical compound shown in the formula V:
Figure BPA00001188361900101
R wherein 71, R 72, R 73And R 74Be that previous embodiments is defined; And A, L, G, Z 1And Z 2Be that aforementioned first embodiment is defined.
In one embodiment, A is selected from H, R 1,-(C=O)-O-R 1, R wherein 1Be selected from aryl; The aryl that replaces; Heteroaryl; The heteroaryl that replaces; The Heterocyclylalkyl of Heterocyclylalkyl or replacement;-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately; Replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl;-C 3-C 12Cycloalkenyl group or replacement-C 3-C 12Cycloalkenyl group.G can be-NH-SO 2-NR 4R 5Or-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group, and R 4And R 5Be selected from independently of one another hydrogen ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8The heterocycle of the heteroaryl of the aryl of alkynyl, aryl, replacement, heteroaryl, replacement, heterocycle, replacement ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Each R 71, R 72, R 73And R 74Be independently selected from hydrogen, halogen ,-NO 2,-CN ,-M-R 4Wherein M does not exist, perhaps O, S, NH, NR 5, aryl, replacement the Heterocyclylalkyl of heteroaryl, Heterocyclylalkyl and replacement of aryl, heteroaryl, replacement, R wherein 4, R 5Be to define as described above.Z 1And Z 2Can be independently selected from F, Cl and Br.
In another embodiment again, A is selected from H, R 1, R wherein 1Be selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately; Replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl;-C 3-C 12Cycloalkenyl group or replacement-C 3-C 12Cycloalkenyl group.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Each R 71, R 72, R 73And R 74Be independently selected from hydrogen, halogen ,-NO 2,-CN.Z 1And Z 2Can be independently selected from F, Cl and Br.
In another embodiment, the present invention relates to formula VI chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Wherein A, G, L, R 1, Z 1And Z 2Define as preamble.In a preferred embodiment, R 1Not hydrogen.
In another embodiment, R 1Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is selected from-C (O)-R 5,-C (O)-O-R 5With-C (O)-NH-R 5, R wherein 5Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L can be selected from C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.G can be-O-R 3,-NH-C (O)-R 3,-NH-SO 2-NH-R 3Or-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.
In another embodiment again, R 1Be selected from the heterocycle of heteroaryl, heterocycle and replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-O-R 5Or-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again, R 1Be selected from the heterocycle of heteroaryl, heterocycle and replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another embodiment, R 1Be selected from the heterocycle of heteroaryl, heterocycle and replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another embodiment again, R 1Be selected from the heterocycle of heteroaryl, heterocycle and replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-R 5, R wherein 5Be what to replace-C 1-C 8Alkyl (for example, the methyl of replacement or ethyl) and by (1) aryl or heteroaryl, (2)-NHC (O)-aryl or-NHC (O)-heteroaryl and optional (3) one or more other substituent groups replace.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again, R 1Be selected from the heterocycle of heteroaryl, heterocycle and replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-R 5, R wherein 5Be the methyl that replaces and at least by (1) aryl or heteroaryl and (2)-NHC (O)-aryl or-NHC (O)-heteroaryl replaces.L is-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In one embodiment, the present invention relates to formula VII chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Figure BPA00001188361900131
Wherein A, G, L, R 1, R 2, Z 1And Z 2Be that aforementioned first embodiment is defined.In one embodiment, R 1And R 2Inequality is a hydrogen.
In another embodiment, R 1And R 2Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group; Perhaps R 1And R 2The carbon atom that connects with their forms and is selected from following loop section: (1) replaces or unsubstituted cycloalkyl, thiazolinyl or heterocycle, perhaps (2) replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle its separately with one or more R 3Condense, wherein each R 3Be independently selected from the heterocycle of heteroaryl, heterocycle or replacement of aryl, heteroaryl, the replacement of aryl, replacement.A can be selected from-C (O)-R 5,-C (O)-O-R 5With-C (O)-NH-R 5, R wherein 5Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L can be selected from C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.G can be-O-R 3,-NH-C (O)-R 3,-NH-SO 2-NH-R 3Or-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.
In a preferred embodiment, R 1And R 2The carbon atom that connects with their forms and is selected from following loop section: (1) replaces or unsubstituted cycloalkyl, thiazolinyl or heterocycle, perhaps (2) replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle its separately with one or more R 3Condense, wherein each R 3Be independently selected from the heterocycle of heteroaryl, heterocycle or replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-O-R 5Or-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another preferred embodiment, R 1And R 2The carbon atom that connects with their forms and is selected from following loop section: (1) replaces or unsubstituted cycloalkyl, thiazolinyl or heterocycle, perhaps (2) replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle its separately with one or more R 3Condense, wherein each R 3Be independently selected from the heterocycle of heteroaryl, heterocycle or replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another preferred embodiment again, R 1And R 2The carbon atom that connects with them forms
Figure BPA00001188361900141
It is optional to be replaced by one or more groups, and each group be independently selected from halogen, hydroxyl, nitro, cyano group, amino, formoxyl ,-C 1-C 8Alkyl or-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another preferred embodiment again, R 1And R 2The carbon atom that connects with their forms and is selected from following loop section: (1) replaces or unsubstituted cycloalkyl, thiazolinyl or heterocycle, perhaps (2) replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle its separately with one or more R 3Condense, wherein each R 3Be independently selected from the heterocycle of heteroaryl, heterocycle or replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.Preferably, R 1And R 2The carbon atom that connects with them forms
Figure BPA00001188361900151
It is optional to be replaced by one or more groups, and each group be independently selected from halogen, hydroxyl, nitro, cyano group, amino, formoxyl ,-C 1-C 8Alkyl or-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl.
In another preferred embodiment, R 1And R 2The carbon atom that connects with their forms and is selected from following loop section: (1) replaces or unsubstituted cycloalkyl, thiazolinyl or heterocycle, perhaps (2) replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle its separately with one or more R 3Condense, wherein each R 3Be independently selected from the heterocycle of heteroaryl, heterocycle or replacement of aryl, heteroaryl, the replacement of aryl, replacement.A is-C (O)-R 5, R wherein 5Be what to replace-C 1-C 8Alkyl (for example, the methyl of replacement or ethyl) and by (1) aryl or heteroaryl, (2)-NHC (O)-aryl or-NHC (O)-heteroaryl and optional (3) one or more other substituent groups replace.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another preferred embodiment again, R 1And R 2The carbon atom that connects with them forms It is optional to be replaced by one or more groups, and each group be independently selected from halogen, hydroxyl, nitro, cyano group, amino, formoxyl ,-C 1-C 8Alkyl or-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl.A is-C (O)-R 5, R wherein 5Be the methyl that replaces and at least by (1) aryl or heteroaryl and (2)-NHC (O)-aryl or-NHC (O)-heteroaryl replaces.L is-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In further embodiment, the present invention relates to formula VIII chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Figure BPA00001188361900161
Wherein V does not exist, and perhaps V is CO, O, S, SO, SO 2, NH, NCH 3Or (CH 2) q
Wherein q is 1,2,3 or 4; And wherein X and Y are independently selected from: aryl; The aryl that replaces; Heteroaryl; The heteroaryl that replaces; Heterocycle; The heterocycle that replaces; And wherein A, G, L, Z 1And Z 2Be that aforementioned first embodiment is defined.
In one embodiment,
Figure BPA00001188361900162
Be selected from
Figure BPA00001188361900163
With
Figure BPA00001188361900164
X wherein 1-X 8Be independently selected from CH and N and X when it is CH 1-X 8Can further be substituted, and Y 1-Y 3Be independently selected from CH, N, NH, S and O and Y when it is CH or NH 1-Y 3Can further be substituted; V be do not exist, CO, O, S, NH or (CH 2) q, wherein q is 1,2 or 3.A can be selected from-C (O)-R 5,-C (O)-O-R 5With-C (O)-NH-R 5, R wherein 5Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G can be-O-R 3,-NH-C (O)-R 3,-NH-SO 2-NH-R 3Or-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again,
Figure BPA00001188361900171
Be selected from
Figure BPA00001188361900173
X wherein 1-X 8Be independently selected from CH and N and X when it is CH 1-X 8Can further be substituted, and Y 1-Y 3Be independently selected from CH, N, NH, S and O and Y when it is CH or NH 1-Y 3Can further be substituted; V be do not exist, CO, O, S, NH or (CH 2) q, wherein q is 1,2 or 3.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again, Be selected from
Figure BPA00001188361900175
With
Figure BPA00001188361900176
X wherein 1-X 8Be independently selected from CH and N and X when it is CH 1-X 8Can further be substituted, and Y 1-Y 3Be independently selected from CH, N, NH, S and O and Y when it is CH or NH 1-Y 3Can further be substituted; V be do not exist, CO, O, S, NH or (CH 2) q, wherein q is 1,2 or 3.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In a preferred embodiment, R 1And R 2The carbon atom that connects with them forms
Figure BPA00001188361900181
X wherein 1-X 8Be independently selected from CH and N and X when it is CH 1-X 8Can further be substituted; V be do not exist, CO, O, S, NH or (CH 2) q, wherein q is 1,2 or 3.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In most preferred embodiment, R 1And R 2The carbon atom that connects with them forms
Figure BPA00001188361900182
Wherein Ra and Rb are independently selected from hydrogen or halogen.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In one embodiment, the present invention relates to formula IX chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Figure BPA00001188361900183
X wherein 1-X 4Be independently selected from CO, CH, NH, O and N; Wherein work as X 1-X 4Any X when being CH or NH 1-X 4Can further be substituted; R wherein 6And R 7Be R independently 3, R wherein 3Be independently selected from:
(i) hydrogen;
(ii) aryl;
The (iii) aryl of Qu Daiing;
(iv) heteroaryl;
(the v) heteroaryl of Qu Daiing;
(vi) heterocycle;
(the vii) heterocycle of Qu Daiing;
(viii)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(ix) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(x)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
(xi) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group; And wherein A, G, L, V, Z 1And Z 2Be defined as the just top embodiment in front.Perhaps, R 6And R 7Can be independently selected from halogen, oxo, sulfo-, nitro, cyano group ,-OR 3,-SR 3,-NR 3R 4,-SOR 3,-SO 2R 3,-NHSO 2R 3,-SO 2NHR 3,-COR 3,-CO 2R 3, (CO) NHR 3,-OCOR 3, OCONHR 3, NHCO 2R 3,-NH (CO) R 3,-NH (CO) NHR 3With-NH (SO 2) NHR 3
In one embodiment, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is selected from-C (O)-R 5,-C (O)-O-R 5With-C (O)-NH-R 5, R wherein 5Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G can be-O-R 3' ,-NH-C (O)-R 3' ,-NH-SO 2-NH-R 3' or-NHSO 2-R 3', R wherein 3' be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-O-R 5Or-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3', R wherein 3' be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3', R wherein 3' be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another embodiment, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another embodiment again, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-R 5, R wherein 5Be what to replace-C 1-C 8Alkyl (for example, the methyl of replacement or ethyl) and by (1) aryl or heteroaryl, (2)-NHC (O)-aryl or-NHC (O)-heteroaryl and optional (3) one or more other substituent groups replace.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-R 5, R wherein 5Be the methyl that replaces and at least by (1) aryl or heteroaryl and (2)-NHC (O)-aryl or-NHC (O)-heteroaryl replaces.L is-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another embodiment, the present invention relates to formula X chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Figure BPA00001188361900211
Y wherein 1-Y 3Be independently selected from CO, CH, NH, N, S and O; And work as Y 1-Y 3Y when being CH or NH 1-Y 3Can further be substituted; Y 4Be selected from C, CH and N; And wherein A, G, L, R 6, R 7, V, Z 1And Z 2Be defined as the just top embodiment in front.
In one embodiment, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is selected from-C (O)-R 5,-C (O)-O-R 5With-C (O)-NH-R 5, R wherein 5Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G can be-O-R 3' ,-NH-C (O)-R 3' ,-NH-SO 2-NH-R 3' or-NHSO 2-R 3', R wherein 3' be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-O-R 5Or-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3', R wherein 3' be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-O-R 5, R wherein 5Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3', R wherein 3' be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another embodiment, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-NH-R 5, R wherein 5Be-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.L is selected from-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
In another embodiment again, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-R 5, R wherein 5Be what to replace-C 1-C 8Alkyl (for example, the methyl of replacement or ethyl) and by (1) aryl or heteroaryl, (2)-NHC (O)-aryl or-NHC (O)-heteroaryl and optional (3) one or more other substituent groups replace.L is selected from-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of aryl, replacement heterocycle ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group.
In another embodiment again, R 6And R 7Be independently selected from heteroaryl, heterocycle, the replacement of aryl, heteroaryl, the replacement of hydrogen, aryl, replacement heterocycle ,-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl ,-C 2-C 8Alkynyl, replacement-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl, replacement-C 2-C 8Alkynyl ,-C 3-C 12Cycloalkyl ,-C 3-C 12Cycloalkenyl group, replacement-C 3-C 12Cycloalkyl and replacement-C 3-C 12Cycloalkenyl group.A is-C (O)-R 5, R wherein 5Be the methyl that replaces and at least by (1) aryl or heteroaryl and (2)-NHC (O)-aryl or-NHC (O)-heteroaryl replaces.L is-C 1-C 8Alkyl or replacement-C 1-C 8Alkyl.Z 1And Z 2Be independently selected from F, Cl and Br.G is-NHSO 2-R 3, R wherein 3Be-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkyl.
Representative compounds of the present invention includes but not limited to the following compounds (table 1) according to formula XI,
Figure BPA00001188361900241
Wherein A, L, Q and the G at each embodiment is described in table 1:
Table 1
Figure BPA00001188361900242
Figure BPA00001188361900271
Figure BPA00001188361900281
Figure BPA00001188361900301
Figure BPA00001188361900311
Representative compounds of the present invention includes but not limited to the following compounds (table 2) according to formula XII:
Figure BPA00001188361900321
R wherein 1And R 2The carbon that connects with them forms R 1R 2, and for each embodiment A, R 1R 2, L and G be defined in Table 2:
Table 2
Figure BPA00001188361900322
Figure BPA00001188361900331
Figure BPA00001188361900341
Figure BPA00001188361900351
Figure BPA00001188361900361
Figure BPA00001188361900371
Figure BPA00001188361900401
Figure BPA00001188361900411
Figure BPA00001188361900421
Other limiting examples of The compounds of this invention is those chemical compounds 202-300 of formula XIII:
Figure BPA00001188361900422
The Rx of each embodiment, L, W and G are defined in Table 3:
Table 3
Figure BPA00001188361900423
Figure BPA00001188361900431
Figure BPA00001188361900441
Figure BPA00001188361900451
Figure BPA00001188361900471
Figure BPA00001188361900481
Figure BPA00001188361900491
Figure BPA00001188361900501
Representative compounds of the present invention includes but not limited to the following compounds (table 4) according to formula XIV:
Figure BPA00001188361900521
The wherein A of each embodiment, L, W 1Be defined in G Table 4:
Table 4
Figure BPA00001188361900522
Figure BPA00001188361900541
Figure BPA00001188361900551
Figure BPA00001188361900561
Figure BPA00001188361900571
Figure BPA00001188361900591
Figure BPA00001188361900601
Figure BPA00001188361900611
Figure BPA00001188361900621
Figure BPA00001188361900641
Figure BPA00001188361900651
Figure BPA00001188361900671
Figure BPA00001188361900681
Figure BPA00001188361900691
Figure BPA00001188361900701
Figure BPA00001188361900711
Figure BPA00001188361900721
Figure BPA00001188361900731
Feature of the present invention also is pharmaceutical composition, and it comprises The compounds of this invention or the acceptable salt of its pharmacy, ester or prodrug.
The compounds of this invention can be used with independent active medicine, perhaps uses with treatment or prevention of hepatitis c infection or with HCV with one or more drug regimens and infects relevant symptom.Comprise with combination being used for infecting the treatment of diseases method that causes that it suppresses the HCV virus replication by direct or indirect system system by HCV with the other medicines of chemical compound combined administration or The compounds of this invention.These comprise for example following medicine: the host immune regulator (for example, interferon-interferon-' alpha ', glycol interferon-α, interferon-beta, interferon-, CpG oligonucleotide or the like) or suppress for example antiviral compound of IMP purine nucleosides dehydrogenase (for example, ribavirin or the like) of host cell function.Also comprise the cytokine of regulating immunologic function.Also comprise vaccine, it comprises the antigen adjuvant combination of HCV antigen or directed anti-HCV.Also comprise such medicine, itself and host cell component interact with by suppressing the translation steps blocking virus protein synthesis of the HCV virus replication that internal ribosome entry site (IRES) causes, and perhaps the blocking virus granule is ripe and discharge the material of HCV P7 or the like for example at the viroporin family of memebrane protein.The other medicines that are used in combination with The compounds of this invention comprise any medicine or drug regimen, and the albumen that they participate in the viral chromosome of virus replication by targeting suppresses HCV and duplicates.These medicines include but not limited to: the inhibitor of HCV RNA RNA-dependent polymerase, for example be described in WO0190121 (A2) or U.S. Patent No. 6,348, nucleoside type AG14361 among 587B1 or WO0160315 or the WO0132153, perhaps non-nucleosidic inhibitors for example is described in the benzimidazole AG14361 among EP 1162196A1 or the WO0204425, the perhaps inhibitor of HCV protease for example BILN2061 or the like, the perhaps inhibitor of HCV unwindase of peptidomimetic type inhibitor for example.
Comprise any medicine or drug regimen with the other medicines of The compounds of this invention combined administration, it suppresses duplicating at other virus of individual co-infected.These medicines include but not limited to be used for infecting the treatment of diseases agent that causes, for example adefovirdipivoxil, lamivudine and tenofovir by hepatitis B (HBV); Perhaps be used for infecting the treatment of diseases agent that causes, for example protease inhibitor: ritonavir, Lopinavir, indinavir, nelfinavir, Saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir by HIV (human immunodeficiency virus) (HIV); Reverse transcriptase inhibitors: zidovudine, lamivudine, Didanosine, stavudine, tenofovir, zalcitabine, Abacavir, efavirenz, nevirapine, delavirdine, TMC-125; Integrase inhibitor: L-870812, S-1360, perhaps entry inhibitor: En Fuwei ground (T-20), T-1249.
Therefore, one aspect of the present invention relates to the method for the infection for the treatment of or preventing to be caused by the virus that comprises RNA, this method comprises to there being the patient who needs this treatment to use the medicine that one or more are selected from host immune regulator and second antiviral agent or its combination jointly, and salt or its combination of the The compounds of this invention of treatment effective dose or chemical compound combination or the acceptable salt of its pharmacy, stereoisomer, tautomer, prodrug, prodrug.The example of host immune regulator is, but be not limited to, interferon-' alpha ', Pegylation-interferon-' alpha ', interferon-beta, interferon-, cytokine, vaccine and comprise antigen and the vaccine of adjuvant, and described second antiviral agent is by suppressing the host cell function relevant with virus replication or the albumen by the targeting viral chromosome suppresses duplicating of HCV.
The further aspect of the present invention relates to the method for the infection for the treatment of or preventing to be caused by the virus that comprises RNA, this method comprises to the common administering therapeutic of the patient who needs this treatment being arranged or alleviate medicine or the drug regimen that symptom that HCV infects comprises liver cirrhosis and hepatitis, and salt or its combination of the The compounds of this invention of treatment effective dose or chemical compound combination or the acceptable salt of its pharmacy, stereoisomer, tautomer, prodrug, prodrug.The present invention provides the method for the infection for the treatment of or preventing to be caused by the virus that comprises RNA more on the other hand, this method comprises to there being the patient who needs this treatment to use one or more treatment patients jointly and infects the medicine of the disease cause by hepatitis B virus (HBV), and salt or its combination of the The compounds of this invention of treatment effective dose or chemical compound combination or the acceptable salt of its pharmacy, stereoisomer, tautomer, prodrug, prodrug.The treatment patient infects the medicine of the disease cause by hepatitis B virus (HBV) can be such as but not limited to L-deoxythymidine, adefovirdipivoxil, lamivudine or tenofovir (tenfovir), or its combination in any.The example that comprises the virus of RNA includes but not limited to hepatitis C virus (HCV).
The present invention provides the method for the infection for the treatment of or preventing to be caused by the virus that comprises RNA on the other hand, this method comprises to there being the patient who needs this treatment to use one or more treatment patients jointly and infects the medicine of the disease cause by human immunodeficiency virus (HIV), and salt or its combination of the The compounds of this invention of treatment effective dose or chemical compound combination or the acceptable salt of its pharmacy, stereoisomer, tautomer, prodrug, prodrug.Described treatment patient can include but not limited to ritonavir by the medicine that human immunodeficiency virus (HIV) infects the disease that causes, Lopinavir, indinavir, viracept see nelfinaivr (nelfmavir), Saquinavir, amprenavir, atazanavir (atazanavir), tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, Didanosine, stavudine, tenofovir, zalcitabine, Abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, En Fuwei ground (enfuvirtide) (T-20) or T-1249, or its combination in any.The example that comprises the virus of RNA includes but not limited to hepatitis C virus (HCV).In addition, the invention provides The compounds of this invention or chemical compound the combination or its treat salt or its combination of acceptable salt shape, stereoisomer or tautomer, prodrug, prodrug, and one or more are selected from the purposes of the medicine of host immune regulator and second antiviral agent or its combination, are used to prepare the particularly medicine of infection with hepatitis C virus of infection that the treatment patient causes by the virus that comprises RNA.The example of this host immune regulator is, but be not limited to, interferon-' alpha ', Pegylation-interferon-' alpha ', interferon-beta, interferon-, cytokine, vaccine and comprise antigen and the vaccine of adjuvant, and described second antiviral agent is by suppressing the host cell function relevant with virus replication or the albumen by the targeting viral chromosome suppresses duplicating of HCV.
When being used for above or other when treatment, The compounds of this invention combination or chemical compound, and one or more can use with purified form as this paper medicine defined above; Perhaps when this type of form exists, be used in combination with the salt of the acceptable salt form of its pharmacy, prodrug, prodrug or its.Perhaps, the compositions of this type of therapeutic agent can be used with pharmaceutical composition, this pharmaceutical composition contains the salt of compound of interest or chemical compound combination or the acceptable salt form of its pharmacy, prodrug or prodrug, and make up one or more this paper medicine defined above, and pharmaceutically acceptable carrier.The virus that this type of pharmaceutical composition can be used for suppressing comprising RNA is duplicating of hepatitis C virus (HCV) particularly, and its mode is by described virus is contacted with described pharmaceutical composition.In addition, this based composition infection of being used for the treatment of or preventing to cause by the viral hepatitis C virus (HCV) that comprises RNA.
Therefore, the further aspect of the present invention relates to treats or prevents by the virus that the comprises RNA method of the infection that causes of hepatitis C virus (HCV) particularly, this method comprises the patient's drug administration compositions to this treatment of needs, this drug regimen comprises salt or its combination of the combination of The compounds of this invention or chemical compound or the acceptable salt of its pharmacy, stereoisomer or tautomer, prodrug, prodrug, one or more are as this paper medicine defined above, and pharmaceutically acceptable carrier.
When combined administration, described treatment can be mixed with in the identical time or the composition isolated of administration in the given time, perhaps with the therapeutic agent of one unit dosage forms administration.
Consider that in this combined therapy the antiviral agent that uses comprises the medicine (chemical compound or biological product) that the virus in effective inhibition mammal forms and/or duplicates, it includes but not limited to disturb the virus in the mammal to form and/or duplicate the medicine of necessary host or virus mechanism.This type of medicine can be selected from another anti-HCV agent; Hiv inhibitor; The HAV inhibitor; With the HBV inhibitor.
Other anti-HCV agent comprises such medicine, and they can reduce or prevention of hepatitis c related symptoms or advancing of disease effectively.This type of medicine includes but not limited to other inhibitor of immunomodulator, HCVNS3 protease inhibitor, HCV polymerase, inhibitor and other anti-HCV agent of another target in the circulation of HCV life, includes but not limited to ribavirin, amantadine, left-handed ribavirin (levovirin) and viramidine.
Immunomodulator comprises such medicine (chemical compound or biological product), and they can make mammiferous immune system reply effectively to be improved or become possibility.Immunomodulator includes but not limited to for example VX-497 (merimepodib of IMP purine nucleosides dehydrogenase inhibitor, VertexPharmaceuticals), I type interferon, II type interferon, sympathetic (consensus) interferon, (the asialo)-interferon that lacks the saliva acidic group, glycol interferon and in conjunction with interferon, include but not limited to include but not limited to the bonded interferon of human albumin with other albumen.I type interferon is one group of interferon, and they comprise the I type interferon of natural and synthetic generation, and II type interferon are all in conjunction with the II receptor all in conjunction with the I receptor.The example of I type interferon include but not limited to [α]-, [β]-, [δ]-, [ω]-and [τ]-interferon, and the example of II type interferon includes but not limited to [γ]-interferon.
HCV NS3 protease inhibitor comprises the medicine (chemical compound or biological product) of the HCV NS3 protease function in effective inhibition mammal.HCV NS3 protease inhibitor includes but not limited to those disclosed chemical compound: WO 99/07733 in the following document, WO 99/07734, WO00/09558, WO 00/09543, WO 00/59929, WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO2005/028501, WO 2005/070955, WO 2006/000085, WO 2006/007700 and WO 2006/007708 (being Boehringer Ingelheim's), WO 02/060926, WO03/053349, WO03/099274, WO03/099316, WO 2004/032827, WO2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410, WO 2005/054430 (being BMS's), WO 2004/072243, WO 2004/093798, WO 2004/113365, WO 2005/010029 (being Enanta's), WO 2005/037214 (Intermune) and WO 2005/051980 (Schering), and be called VX-950, candidate's product of ITMN-191 and SCH 503034.
The HCV AG14361 comprises the medicine (chemical compound or biological product) of effective inhibition HCV polymerase function.This type of inhibitor comprises but is not limited to the non-nucleoside and the nucleosidic inhibitors of HCV NS5B polymerase.The example of HCV AG14361 includes but not limited to those disclosed chemical compound: WO 02/04425 in the following document, WO 03/007945, WO 03/010140, WO 03/010141, WO 2004/064925, WO 2004/065367, WO 2005/080388 and WO 2006/007693 (being Boehringer Ingelheim's), WO 2005/049622 (Japan Tobacco), WO2005/014543 (Japan Tobacco), WO 2005/012288 (Genelabs), WO2004/087714 (IRBM), WO 03/101993 (Neogenesis), WO 03/026587 (BMS), WO 03/000254 (Japan Tobacco), with WO 01/47883 (JapanTobacco), and clinical candidate's product XTL-2125, HCV 796, R-1626 and NM 283.
The inhibitor of another target in the circulation of HCV life comprises such medicine (chemical compound or biological product), and they effectively suppress the formation of HCV and/or duplicate, rather than by suppressing the function of HCV NS3 protease.This type of medicine can disturb HCV to form and/or duplicate necessary host or HCV virus mechanism.The inhibitor of another target in the circulation of HCV life comprises but is not limited to entry inhibitor, inhibition is selected from the medicine of the target of unwindase, NS2/3 protease and internal ribosome entry site (IRES), and disturbs other viral target to include but not limited to the medicine of NS5A albumen and the proteic function of NS4B.
What may occur is that patient's possibility co-infected hepatitis C virus and one or more other viruses include but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV).Therefore also consider the combined therapy method of this type of co-infected of treatment, its mode is to use The compounds of this invention jointly, and at least a in hiv inhibitor, HAV inhibitor and the HBV inhibitor.
According to another embodiment again, pharmaceutical composition of the present invention can further comprise the inhibitor that other target in the circulation of HCV life includes but not limited to unwindase, polymerase, metalloproteases and internal ribosome entry site (IRES).
According to another embodiment, pharmaceutical composition of the present invention can further comprise another antiviral antifungal or agent, antibacterial, anticarcinogen, perhaps immunomodulator, perhaps another therapeutic agent.
According to another embodiment again, the present invention includes by The compounds of this invention from effective dose to described experimenter or the acceptable salt of its pharmacy, ester or the prodrug of using and in the experimenter of this treatment of needs, treat the method for viral infection such as but not limited to hepatitis C infection.
According to further embodiment, the present invention includes the method for in the experimenter of this treatment of needs, treating hepatitis C infection by pharmaceutical composition of the present invention from amount of suppression to described experimenter that use anti-HCV virus effective dose or.
Another embodiment of the present invention comprises by making biological sample contact the method for handling biological sample with The compounds of this invention.
The present invention is to use arbitrary synthetic method described herein to prepare the method for arbitrary chemical compound described herein more on the other hand.
Be used for the metabolism that Cytochrome P450 monooxygenase inhibitor expectation of the present invention suppresses The compounds of this invention.Therefore, this Cytochrome P450 monooxygenase inhibitor should be the metabolic amount of effective Profilin enzyme inhibitor.Correspondingly, this CYP inhibitor should be used with such amount, and this amount makes the bioavailability of the bioavailability of protease inhibitor when not having the CYP inhibitor compare increase.
In one embodiment, the invention provides the method for the pharmacokinetics of improving The compounds of this invention.The benefit of improving the pharmacokinetics of medicine is (US2004/0091527 well known in the art; US 2004/0152625; US 2004/0091527).Correspondingly, one embodiment of the invention provides the method for this present invention of inhibitor chemical compound of using CYP3A4.Another embodiment of the present invention has supplied to use the method for the inhibitor of The compounds of this invention and isozyme 3A4 (" CYP3A4 "), isozyme 2C19 (" CYP2C19 "), isozyme 2D6 (" CYP2D6 "), isoazyne 1 A2 (" CYP1A2 "), isozyme 2C9 (" CYP2C9 ") or isozyme 2E1 (" CYP2E1 ").In preferred embodiments, described CYP inhibitor preferably suppresses CYP3A4.The arbitrary CYP inhibitor that improves the pharmacokinetics of relevant NS3/4A protease all can be used for the inventive method.These CYP inhibitor comprise but are not limited to ritonavir (WO 94/14436), ketoconazole, triacetyloleandomycin, 4-methylpyrazole, ciclosporin, chlorethiazol, cimetidine, Itraconazole, fluconazol, miconazole, Fluvoxamine, fluoxetine, nefazodone, Sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir, Saquinavir, Lopinavir, delavirdine, erythromycin ethylsuccinate, VX-944 and VX-497.Preferred CYP inhibitor comprises ritonavir, ketoconazole, triacetyloleandomycin, 4-methylpyrazole, ciclosporin and chlorethiazol.
Be appreciated that the mode by single patient packing or the patient's packing by each preparation (in packing instruction in contain the instruction of the correct use of indication patient), combined administration of the present invention is that the present invention wishes the feature that increases.
Further aspect is a kind of packing according to the present invention, comprises in this packing to have The compounds of this invention and CYP inhibitor of the present invention and information inset at least, contains the instruction of using the present invention's combination in this inset that stops.In alternate embodiment of the present invention, described drug packages further comprises one or more other medicines as herein described.These one or more other medicine can be provided in same package or separate in the packing.
This relates on the other hand for the patient and is used for the treatment of the packing medicine box that HCV infects or prevention HCV infects, and this medicine box comprises: the single or multiple pharmaceutical preparatioies of each ingredient; During preservation or hold the container of this pharmaceutical preparation before using; And the description that is used for carrying out medicament administration in the mode that effective treatment or prevention HCV infect.
Correspondingly, the invention provides to be used for simultaneously or to use successively the medicine box of NS3/4A protease inhibitor of the present invention and CYP inhibitor (with optional other medicines) or its derivant for preparing in a usual manner.Usually, this medicine box will comprise, for example various inhibitor and the optional compositions (and in one or more pharmaceutical preparatioies) of other medicines in pharmaceutically acceptable carrier and the description of writing that is used for the while or uses successively.
In another embodiment, provide the medicine box of packing, it contains one or more and is used for the dosage form that the oneself uses; Vessel form, preferred sealing is used for holding this dosage form in preservation with before using; And be used for the description that the patient carries out medicament administration.This description is normally in package insert, label and/or the description of writing on other assembly on this medicine box, and these one or more dosage forms are as described herein.Each dosage form can be held respectively, as in a metal forming-plastics tabletting and each dosage form in individual unit lattice or blister, be separated from each other; Perhaps this dosage form can be contained in the single container, as in plastic bottle.Medicine box of the present invention also generally includes and is used to pack the instrument that this single medicine box assembly promptly is total to this dosage form, this vessel form that uses and the description of writing.This type of wrapping tool can be the form of millboard or carton, plastics or paper tinsel bag etc.
Definition
Classify the definition that is used to describe various terms of the present invention down as.These definition are applicable to the term that uses in from start to finish in this description and claim, unless have in addition respectively in particular case or as the qualification than the part of macoradical.
Term " viral infection " be instigate virus for example hepatitis C virus (HCV) be incorporated in the cell or tissue.Usually, Bing Du introducing also with duplicate relevant.Can by measure to measure biofluid for example the antiviral antibody titre in the blood for example use enzyme immunoassay to measure viral infection.Other suitable diagnostic method comprise based on the technology of molecule for example RT-PCR, directly the heterozygosis capture assay, based on amplification of nucleotide sequence or the like.Virus can infect for example liver of organ, and causes disease for example hepatitis, liver cirrhosis, chronic hepatopathy and hepatocarcinoma.
Term " anticarcinogen " is meant a kind of chemical compound or medicine that can prevent or suppress cancer development.The example of this type of medicine comprises cisplatin, actinomycin D, amycin, vincristine, vinblastine, etoposide, Amsiacrine, mitoxantrone, teniposide, taxol, colchicine, Ciclosporin A, phenothiazines or thioxanthene class (thioxantheres).
Term " antifungal " will be used to describe the chemical compound that is used for the treatment of fungal infection, but not comprise the prodrug of 3-AP of the present invention, 3-AMP or 3-AP and 3-AMP.Antifungal of the present invention comprises for example terbinafine, fluconazol, Itraconazole, posaconazole, clotrimazole, griseofulvin, nystatin, Tolnaftate (tolnaftate), Caspofungin, amphotericin B, liposome amphotericin b and amphotericin B lipid complex.
Term " antibacterial " is meant that microorganisms is to suppress the naturally occurring antibiotic of other growth of microorganism, and laboratory is synthetic or the medicine of modification, they have sterilization or bacteriostatic activity, for example, beta-lactam antibacterial, glycopeptide class, Macrolide, quinolones, Tetracyclines and aminoglycosides.Usually, if a kind of antibacterial is an antibacterial, then it represents that this medicine can end bacterial cell growth (but not can kill bacteria) basically; If this medicine is an antibacterial, then it represents that this medicine can kill bacteria cell (and can end growth before killing this antibacterial).
Term " immunomodulator " is meant that expression changes any material of the work of experimenter's body fluid or cell immune system.This type of immunomodulator comprises inhibitor, interferon, interleukin, prostaglandin, steroid, 17-hydroxy-11-dehydrocorticosterone, colony stimulating factor, chemotactic factor of the inflammation of mast cell mediated etc.
Term " C 1-C 6Alkyl " or " C 1-C 8Alkyl ", as be used for this paper, being meant saturated straight or branched alkyl, it contains 1 to 6 or 1 to 8 carbon atom respectively.C 1-C 6The example of alkyl group includes but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, neopentyl, n-hexyl group; C 1-C 8The example of alkyl group includes but not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, the tert-butyl group, neopentyl, n-hexyl, heptyl, octyl group group.
Term " C 2-C 6Thiazolinyl " or " C 2-C 8Thiazolinyl ", as be used for this paper, be meant that wherein this hydrocarbon partly has at least one carbon-to-carbon double bond, and contains 2-6 or 2-8 carbon atom respectively derived from the group of hydrocarbon part.Alkenyl group includes but not limited to, for example, and vinyl, acrylic, cyclobutenyl, 1-methyl-2-butene-1-base, heptenyl, octenyl etc.
Term " C 2-C 6Alkynyl " or " C 2-C 8Alkynyl ", as be used for this paper, be meant that wherein this hydrocarbon partly has at least one carbon-to-carbon three key, and contains 2-6 or 2-8 carbon atom respectively derived from the group of hydrocarbon part.Typically alkynyl group includes but not limited to, for example, and acetenyl, 1-propinyl, ethyl acetylene base, heptyne base, octyne base etc.
Term " C 3-C 8-cycloalkyl " or " C 3-C 12-cycloalkyl ", as be used for this paper, be meant group derived from monocycle shape or polycyclic saturated carbon ring, wherein this saturated carbon ring chemical compound has 3-8 or 3-12 annular atoms respectively.C 3-C 8The example of-cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, cyclopenta and ring octyl group; C 3-C 12The example of-cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, dicyclo [2.2.1] heptyl and dicyclo [2.2.2] octyl group.
Term " C 3-C 8-cycloalkenyl group " or " C 3-C 12-cycloalkenyl group ", as be used for this paper, be meant derived from monocycle shape or polycyclic and have the group of the carbocyclic compound of at least one carbon-to-carbon double bond that wherein this carbocyclic compound has 3-8 or 3-12 annular atoms respectively.C 3-C 8The example of-cycloalkenyl group includes but not limited to cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base etc.; C 3-C 12The example of-cycloalkenyl group includes but not limited to cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl, cyclo-octene base etc.
Term " aryl ", as be used for this paper is meant monocycle with one or two aromatic rings-or bicyclic carbocyclic loop systems, and it includes but not limited to phenyl, naphthyl, tetralyl, indanyl, indenyl etc.
Term " aryl alkyl ", as be used for this paper, be meant and be connected with the C of aromatic ring 1-C 3Alkyl or C 1-C 6Alkyl residue.Example includes but not limited to benzyl, phenethyl etc.
Term " heteroaryl ", as be used for this paper, be meant single-, two-or three-ring-type aromatic group or ring, it has 5-10 annular atoms, wherein at least one annular atoms is selected from S, O and N; Wherein any N that contains in this ring or S can choose wantonly oxidized.Heteroaryl include but not limited to pyridine radicals, pyrazinyl, pyrimidine radicals, pyrrole radicals, pyrazolyl, imidazole radicals, thiazolyl, Azoles base, different
Figure BPA00001188361900812
Azoles base, thiadiazolyl group,
Figure BPA00001188361900813
Di azoly, thienyl, furyl, quinolyl, isoquinolyl, benzimidazolyl, benzo Azoles base, quinoxalinyl etc.
Term " heteroaryl alkyl ", as be used for this paper, be meant and be connected with the C of heteroaryl ring 1-C 3Alkyl or C 1-C 6Alkyl residue.Example includes but not limited to pyridylmethyl, pyrimidinylethyl etc.
Should be appreciated that aryl, heteroaryl, alkyl etc. can further be substituted.In some cases, each substituent group in the part that replaces is also optional to be replaced by one or more groups, and each group is independently selected from-F ,-Cl ,-Br ,-I ,-OH ,-NO 2,-CN or-NH 2
According to the present invention, the heteroaryl of aryl, heteroaryl and the replacement of any aryl described herein, replacement can be any aromatic group.Aromatic group can be substituted or not be substituted.
Should be appreciated that any alkyl described herein, thiazolinyl, alkynyl, cycloalkyl and cycloalkenyl group part also aliphatic group, alicyclic group or heterocyclic group." aliphatic group " is non-aromatics part, and it can contain the combination in any of carbon atom, hydrogen atom, halogen atom, oxygen, nitrogen or other atom, and optional one or more unsaturated units, for example two keys and/or three key of containing.Aliphatic group can be straight chain, side chain or ring-type, and preferably contains and have an appointment 1 to about 24 carbon atoms, and more particularly about 1 to about 12 carbon atoms.Except aliphatic alkyl, aliphatic group for example comprises that multi-alkoxy alkyl is poly alkylene glycol (polyalkylene glycols) for example, polyamine class and poly-imines class.This type of aliphatic group can further be substituted.Should be appreciated that aliphatic group can use with alkyl as herein described, thiazolinyl, alkynyl, alkylidene, alkenylene and the replacement of alkynylene group.
Term " alicyclic ", as be used for this paper, be meant group derived from monocycle or multi-ring saturated carbon ring chemical compound.Example includes but not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, dicyclo [2.2.1] heptyl and dicyclo [2.2.2] octyl group.This type of alicyclic group can further be substituted.
Term " Heterocyclylalkyl " and " heterocycle " can exchange use, and be meant non-aromatics 3-, 4-, 5-, 6-or 7-unit ring or two-or the system that condenses of three-cyclic group, wherein (i) each ring contains the individual oxygen that is independently selected from of 1-3, the hetero atom of sulfur and nitrogen, (ii) each 5-unit ring has 0-1 two keys and each 6-unit ring has 0-2 two keys, (iii) oxygen and sulfur heteroatom can be chosen wantonly oxidized, (iv) nitrogen heteroatom can be chosen wantonly by quaternized, (iv) above any be fused to phenyl ring that encircles, (v) all the other annular atomses are carbon atoms, and it can be chosen wantonly by oxo-replacement.Representational heterocycloalkyl include but not limited to [1,3] dioxolanes, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidyl, piperazinyl,
Figure BPA00001188361900841
Oxazolidinyl, different
Figure BPA00001188361900842
Oxazolidinyl, morpholinyl, Thiazolidine, isothiazolidine, quinoxalinyl, pyridazine ketone group and tetrahydrofuran base.This type of heterocyclic radical can further be substituted, the heterocycle that obtains replacing.
Obviously, in the different embodiment of the present invention, described replacement or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, cycloalkenyl group, cycloalkynyl radical, aryl alkyl, heteroaryl alkyl and Heterocyclylalkyl will be monovalent or bivalence.Therefore, alkylidene, alkenylene and alkynylene, cycloalkylidene, inferior cycloalkenyl group, inferior cycloalkynyl radical, inferior aralkyl, inferior heteroarylalkyl and inferior heterocycloalkyl are included in the above-mentioned definition, and are applicable to this paper with suitable atomicity is provided chemical formula.
Term " hydroxyl activated group ", as be used for this paper, being meant unsettled chemical part, it is known in the art, can make the hydroxyl activation and break away from so that it is for example replacing or eliminating between the reaction period in building-up process.The example of hydroxyl activated group includes but not limited to methanesulfonate, tosylate, trifluoromethanesulfonic acid root, right-the nitrobenzoyl acid group, phosphate radical etc.
Term " activatory hydroxyl ", as be used for this paper, be meant that by the hydroxyl of hydroxyl activated group defined above described hydroxyl activated group comprises for example methanesulfonate, tosylate, trifluoromethanesulfonic acid root, right-the nitrobenzoyl acid group, phosphate radical.
Term used herein " hydroxyl of protection " is meant by the hydroxyl of the hydroxy-protective group of above definition protection, comprises benzoyl, acetyl group, trimethyl silyl, triethylsilyl, methoxy blocking group.
Term used herein " halo " and " halogen " are meant the atom that is selected from fluorine, chlorine, bromine and iodine.
Chemical compound described herein contains one or more asymmetric center, and therefore produce enantiomer, non-corresponding isomer, reach other stereomeric form, its can be defined as according to the absolute stereo chemistry (R)-or (S)-, perhaps (D)-or (L)-aminoacid.This invention is intended to the isomer that comprises that all these are possible and their racemic and optically pure form.Optical isomer can be by their corresponding optical activity precursors by aforesaid method, or prepares by splitting racemic mixture.In the presence of resolution reagent, split by chromatography or by repeated crystallization or by the combination that well known to a person skilled in the art these technology.Be found in Jacques about the details that splits, et al., Enantiomers Racemates, and Resolutions(John Wiley﹠amp; Sons, 1981).When chemical compound described herein contains olefinic double bonds or other geometric asymmetry center, and except as otherwise noted, it is meant that chemical compound comprises two kinds of E and Z geometric isomers.Similarly, all tautomeric forms are also intended to be included.The selection of the configuration of any carbon-to-carbon double bond that this paper occurs is for the purpose of the convenience rather than be intended to name a kind of specific configuration, unless so statement in the text; Therefore to be described as trans carbon-to-carbon double bond ad arbitrium can be mixture cis, trans or both arbitrary proportions to this paper.
Term used herein " experimenter " is meant mammal.Therefore the experimenter is meant, for example, and Canis familiaris L., cat, horse, cattle, pig, Cavia porcellus or the like.Preferably the experimenter behaves.When the experimenter is a man-hour, the experimenter here can be the patient.
Term described herein " the acceptable salt of pharmacy " is meant the salt of the chemical compound that forms by method of the present invention, it is in the scope that the doctor judges, be suitable for contacting with zootic tissue with the people and not having unsuitable toxicity, stimulation, anaphylaxis or the like, and have rational interests/danger ratio.The acceptable salt of pharmacy is well known in the art.
Term used herein " hydroxy-protective group " is meant that the hydroxyl of protecting known in the art is to avoid the unstable chemical part of unwanted reaction in building-up process.After described building-up process, hydroxy-protective group described herein can be sloughed by selectivity.Hydroxy-protective group known in the art is in following document summarized introduction: T.H.Greene and P.G., and S.M.Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley﹠amp; Sons, New York (1999).The example of hydroxy-protective group comprises benzyloxycarbonyl; 4-nitro benzyloxycarbonyl; 4-bromo-benzyloxy-carbonyl; 4-methoxyl group benzyloxy base carbonyl; methoxycarbonyl; tert-butoxycarbonyl; isopropoxy carbonyl; diphenyl methoxy base carbonyl; 2; 2; 2-trichlorine ethoxy carbonyl; 2-(trimethyl silyl) ethoxy carbonyl; 2-furfuryl group oxygen base carbonyl; allyloxy carbonyl; acetyl group; formoxyl; chloracetyl; trifluoroacetyl group; the methoxyl group acetyl group; the phenoxy group acetyl group; benzoyl; methyl; the tert-butyl group; 2; 2; 2-three chloroethyls; 2-trimethyl silyl ethyl; 1; 1-dimethyl-2-acrylic; 3-methyl-3-cyclobutenyl; pi-allyl; benzyl; to the methoxy-benzyl diphenyl methyl; trityl group (trityl); tetrahydrofuran base; methoxy; methylthiomethyl; benzyloxymethyl; 2; 2,2-trichlorine ethoxyl methyl; 2-(trimethyl silyl) ethoxyl methyl; mesyl; p-toluenesulfonyl; trimethyl silyl; triethylsilyl; triisopropyl silicyl etc.Preferred hydroxy-protective group of the present invention have acetyl group (Ac or-C (O) CH 3), benzoyl (Bz or-C (O) C 6H 5) and trimethyl silyl (TMS or-Si (CH 3) 3).People such as Berge describe the acceptable salt of pharmacy in detail at J.Pharmaceutical Sciences among the 66:1-19 (1977).These salt can perhaps can prepare separately with the reaction of suitable organic acid by free alkali functional group in the final separation of The compounds of this invention and purification step in in-situ preparing.The example of the acceptable salt of pharmacy include but not limited to the non-toxic acid addition salts for example amino with mineral acid (for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid and perchloric acid) or the salt that forms with organic acid (for example acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid), perhaps use the salt of other method (for example ion exchange) preparation of this area.The acceptable salt of other pharmacy includes but not limited to adipate, alginate, Ascorbate, aspartate, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphorate, camsilate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, gluconate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2-hydroxyl-esilate, Lactobionate, lactate, laruate, lauryl sulfate, malate, maleate, malonate, mesylate, the 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalates, palmitate, embonate, pectinic acid salt, persulfate, 3-phenylpropionic acid salt, phosphate, picrate, Pivalate, propionate, stearate, succinate, sulfate, tartrate, rhodanate, tosilate, the hendecane hydrochlorate, valerate etc.Representational alkaline or alkaline-earth salts comprises sodium salt, lithium salts, potassium salt, calcium salt, magnesium salt etc.Under the suitable situation, the acceptable salt of other pharmacy comprises with counter ion counterionsl gegenions and forms nontoxic ammonium, quaternary ammonium and amine cation, for example halogenide, hydroxide, formic acid esters, sulfate, phosphate, nitrate, the alkylsulfonate with 1-6 carbon atom and arylsulphonate.
Term used herein " amido protecting group " is meant that the amine groups of protecting known in the art is to avoid the unstable chemical part of unwanted reaction in building-up process.After described building-up process, amido protecting group described herein can be sloughed by selectivity.Amido protecting group known in the art is in following document summarized introduction: T.H.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, the 3rd edition, John Wiley﹠amp; Sons, New York (1999).The example of amido protecting group includes but not limited to tert-butoxycarbonyl, 9-fluorenyl methoxy carbonyl, benzyloxycarbonyl etc.
Term used herein " the acceptable ester of pharmacy " but be meant the chemical compound of hydrolysis in the body that forms by the inventive method, comprise being easy in human body, decompose those that obtain parent compound or its salt.Suitable ester group include but not limited to by the acceptable aliphatic carboxylic acid of pharmacy (especially alkanoic acid, alkenoic acid, aphthenic acids and alkanedioic acid) deutero-those, wherein each alkyl or alkenyl part preferably is no more than 6 carbon atoms.The example of concrete ester includes but not limited to formic acid esters, acetas, propionic ester, butyrate, acrylate and ethyl succinate.
Term described herein " pharmacy acceptable prodrugs " is meant those prodrugs of the chemical compound that forms by the inventive method, it is in the scope that the doctor judges, be suitable for contacting with zootic tissue and do not have unsuitable toxicity, stimulation, anaphylaxis or the like with the people, and has rational interests/risk ratio, with the effective aim purposes, and the possible zwitterionic form of The compounds of this invention." prodrug " used herein is meant such chemical compound, and it changes by metabolism mode (for example by hydrolysis) in vivo, obtains the described any compound of general formula of the present invention.Various forms of prodrugs are well known in the art, for example, are discussed in Bundgaard, (ed.), and Design ofProdrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol.4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). " Chapter 5,113-191 (1991) for Design andApplication of Prodrugs, Textbook of Drug Design and Development; Bundgaard, et a1., Journal of Drug DeliverReviews, 8:1-38 (1992); Bundgaard, J.of Pharmaceutical Sciences, 77:285 et seq. (1988); Higuchi and Stella (eds.) Prodrugs as Novel DrugDelivery Systems, American Chemical Society (1975); And Bernard Testa﹠amp; Joachim Mayer, and " Hydrolysis In Drug And Prodrug Metabolism:Chemistry, Biochemistry And Enzymology, " John Wiley and Sons, Ltd. (2002).
Term " acyl group " comprises the residue derived from acid (including but not limited to carboxylic acid, carbamic acid, carbonic acid, sulfonic acid and phosphorous acid).Example comprises aliphatic carbonyl, aromatics carbonyl, aliphatic sulfonyl, aromatics sulfinyl, aliphatic sulfinyl, aromatic phosphate acid ester and aliphatic phosphate ester.The example of aliphatic carbonyl includes but not limited to acetyl group, propiono, 2-acetyl fluoride base, bytyry, 2-hydroxyacetyl or the like.
Term used herein " aprotic solvent " is meant the solvent to the active relative inertness of proton (promptly not as proton donor).Example includes but not limited to for example hydro carbons (for example hexane and toluene), halogenated hydrocarbons (for example dichloromethane, dichloroethanes, chloroform etc.), heterocyclic compound (for example oxolane and N-Methyl pyrrolidone) and ethers (for example ether, bi-methoxy methyl ether).This kind solvent is well known in the art, and for specific compound and reaction condition preferred indivedual solvents or its mixture, this depends on for example following various factors: the dissolubility of reagent, the reactivity of reagent and preferred temperature range.The further discussion of aprotic solvent can be referring to organic chemistry textbook or monograph, for example: Organic Solvents Physical Properties and Methods of Purification, the 4th edition, chief editor John A.Riddick et al., Vol.II, Techniques of Chemistry Series, John Wiley﹠amp; Sons, NY, 1986.
Term used herein " protogenic organic solvent " or " proton solvent " are meant that trend provides the solvent of proton, for example alcohol, for example methanol, ethanol, propanol, isopropyl alcohol, butanols, the tert-butyl alcohol etc.This kind solvent is well known in the art, and for specific compound and reaction condition preferred indivedual solvents or its mixture, this depends on for example following various factors: the dissolubility of reagent, the reactivity of reagent and preferred temperature range.The further discussion of protogenic solvent can be referring to organic chemistry textbook or monograph, for example: Organic Solvents Physical Properties and Methods of Purification, the 4th edition, chief editor John A.Riddick et al., Vol.II, Techniques of Chemistry Series, John Wiley﹠amp; Sons, NY, 1986.
The substituent group of the present invention anticipation and the combination of variant only are those that cause that stable compound forms.Term used herein " stable " be meant have be enough to allow the stability of producing with and keep the chemical compound of the purpose (for example, treatment or prevention are applied to the experimenter) that the chemical compound integrity of enough time is used for describing in detail here.
Synthetic chemical compound can be by separating in the reactant mixture and passing through such as column chromatography further, and high pressure liquid chromatography or recrystallization method carry out purification.In addition, order or the order that can choose wantonly of different synthesis step produces the purpose chemical compound.In addition, here the solvent of Miao Shuing, temperature, response time etc. only are used for illustrative purposes, and the variation of reaction condition can produce purpose bridging macro ring product of the present invention.The synthetic synthetic chemistry of chemical compound transformed and protecting group method (protect and go and protect) comprises being used for of here describing, and for example was described in R.Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W.Greene and P.G.M.Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L.Fieser and M.Fieser, Fieser and Fieser ' s Reagents for Organic Synthesis, John Wiley and Sons (1994); And L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, those among the John Wileyand Sons (1995).
Chemical compound of the present invention can be modified through adding different functional groups by synthetic method described herein, strengthens optionally biological characteristics.These modifications comprise increase enter the biosystem of giving (for example, blood, lymphsystem, central nervous system) biology infiltration, increase oral utilization rate, increase dissolubility and use by injection allowing, change metabolism and change those of discharge rate.
Pharmaceutical composition
Pharmaceutical composition of the present invention comprises The compounds of this invention and one or more pharmaceutically acceptable carriers for the treatment of effective dose.Term used herein " pharmaceutically acceptable carrier " is meant the formulation adjuvant of nontoxic inert solid, semisolid or liquid filling agent, diluent, coating material or any kind.The part example that can be used as the material of pharmaceutical acceptable carrier has sugar, for example lactose, Fructus Vitis viniferae and sucrose; Starch, for example corn starch and potato starch; Cellulose and derivant thereof, for example sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; Powdered tragacanth; Fructus Hordei Germinatus; Gelatin; Pulvis Talci; Excipient, for example cocoa butter and suppository wax; Oil, for example Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum sesami, olive oil, Semen Maydis oil and soybean oil; Glycols, for example propylene glycol; Ester, for example ethyl oleate and ethyl laurate; Agar; Buffer agent, for example magnesium hydroxide and aluminium hydroxide; Alginic acid; Apirogen water; Isotonic saline solution; Ringer's mixture; Ethanol and phosphate buffered solution; According to recipe design person's judgement, other nontoxic compatible lubricant (for example sodium lauryl sulfate and magnesium stearate), and coloring agent, releasing agent, coating materials, sweeting agent, flavoring agent, aromatizing agent, antiseptic and antioxidant also can add in the compositions.Pharmaceutical composition of the present invention can per os, in the rectum, parenteral, brain pond, intravaginal, intraperitoneal, part (as powder, ointment or drop), buccal, mouthspray or intranasal spraying administration of human or other animal.
Pharmaceutical composition of the present invention can per os, parenteral, suction spraying, part, per rectum, per nasal, through the oral cavity, transvaginal or through implanting the storage storehouse, preferred oral administration or use through injection.Pharmaceutical composition of the present invention can contain the non-toxicity pharmaceutically acceptable carrier of any routine, auxiliary agent or solvent.In some cases, the pH of preparation can regulate with the acceptable acid of pharmacy, alkali or buffer agent, to strengthen the chemical compound prepared or it delivers the stability of form.That term parenteral used herein comprises is subcutaneous, in the Intradermal, intravenous, intramuscular, intraarticular, intra-arterial, synovial cavity, in the breastbone, in the sheath, intralesional (intralesional) and intracranial injection or infusion techniques.
The liquid oral dosage form comprises the acceptable Emulsion of pharmacy, microemulsion, solution, suspensoid, syrup and elixir.Remove the active ingredient beyond the region of objective existence, liquid dosage form can also comprise this area inert diluent (for example water or other solvent), solubilizing agent and emulsifying agent commonly used, for example ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzoic acid benzyl ester, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oil (especially Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol, Polyethylene Glycol, the fatty acid ester of sorbitan and their mixture.Except that inert diluent, Orally administered composition also can comprise adjuvant, for example wetting agent, emulsifying agent and suspending agent, sweeting agent, flavoring agent and aromatizing agent.
Ejection preparation (for example aseptic injection aqueous or oiliness suspensoid) can be prepared according to known technology with suitable dispersant or wetting agent and suspending agent.Aseptic injection preparation can also be nontoxic parenteral acceptable diluent or aseptic injectable solution agent, suspensoid or the Emulsion in the solvent, for example solution in the 1,3 butylene glycol.In acceptable solvent and solvent, can make water, Ringer's mixture, U.S.P. and isotonic sodium chlorrde solution.In addition, aseptic expressed oi is usually as solvent or suspension media.For this purpose, can use the expressed oi of any gentleness, comprise synthetic monoglyceride or diglyceride.In addition, fatty acid (for example oleic acid) also uses in ejection preparation.
Ejection preparation for example can followingly be sterilized: be detained filter by antibacterial and filter, perhaps biocide is added in the form of aseptic solid composite, this aseptic solid composite can face with preceding dissolving be distributed to sterilized water or other aseptic injection medium in.
In order to prolong drug effect, wish to slow down absorption subcutaneous or the intramuscular injection medicine usually.Can use the crystal of poorly water-soluble or the liquid suspension of amorphous substance to reach this purpose.The drug absorption rate depends on rate of dissolution like this, and this depends on crystal size and crystal form.Perhaps, thus with medicine dissolution or be suspended in the oiliness solvent absorption that postpones the parenteral administered agents.Make injection storage storehouse dosage form by the microcapsule skeleton that in biodegradable polymer (for example polyactide-poly-Acetic acid, hydroxy-, bimol. cyclic ester), forms medicine.The character that depends on the concrete polymer of drug/polymer ratio and use can be controlled release rate of drugs.The example of other biodegradable polymer comprises poly-(ortho esters) and poly-(anhydride).Also pharmaceutical pack can be embedded in liposome or the microemulsion compatible and preparation storage storehouse ejection preparation with bodily tissue.
The compositions of rectum or vagina administration is preferably suppository, suppository can be mixed with by The compounds of this invention and suitable non-stimulated excipient or carrier, for example (they are solids in room temperature with cupu oil, Polyethylene Glycol or suppository wax, and be liquid under body temperature, therefore in rectum or vaginal canal fusing, discharge reactive compound) mix.
Comprise capsule, tablet, pill, powder and granule for Orally administered solid dosage forms.In this type of solid dosage forms, reactive compound and at least a inert, acceptable excipient of pharmacy or carrier for example sodium citrate or dicalcium phosphate and/or following material mix: a) filler or bulking agent starch for example, lactose, sucrose, glucose, mannitol and silicic acid, b) binding agent carboxymethyl cellulose for example, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum, c) wetting agent glycerol for example, d) disintegrating agent agar for example, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, certain this silicate and sodium carbonate, e) solution blocker paraffin for example, f) absorption enhancer quaternary ammonium compound for example, g) for example spermol and glyceryl monostearate of wetting agent, h) for example Kaolin and bentonite of absorbent, and i) lubricant Talcum for example, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and their mixture.Under the situation of capsule, tablet and pill, described dosage form can also contain buffer agent.
The solid composite of similar type can also be as the filler of soft and hard filled capsules, for example uses lactose and high component Polyethylene Glycol etc. as excipient.
Reactive compound also can constitute microencapsulation form with one or more above-mentioned excipient.Solid dosage forms tablet, dragee, capsule, pill and granule can be used coating and shell, for example enteric coating, release control coating and known other coating of pharmacy formulation art.In this type of solid dosage forms, reactive compound can for example sucrose, lactose or starch mix with at least a inert diluent.As conventional practice, this type of preparation also can comprise other material except that inert diluent, for example film-making lubricant and other film-making auxiliary agent (for example magnesium stearate and microcrystalline Cellulose).When being capsule, tablet and pill, these dosage forms also can comprise buffer agent.They also can be chosen wantonly and comprise opacifier, only also can be or preferably in the compositions of some part release of active ingredients of intestinal, optionally discharge with delayed mode.The example of operable embedding composition comprises polymer and wax.
The dosage form of part or transdermal administration The compounds of this invention comprises ointment, paste, emulsifiable paste, lotion, gel, powder, solution, spray, inhalant or patch.Under aseptic condition, active component and pharmaceutically acceptable carrier and any antiseptic that may need or buffer agent are mixed.Eye preparation, ear drop, eye ointment, powder and solution are also included within the scope of the invention.
Remove active ingredient beyond the region of objective existence of the present invention, ointment, paste, emulsifiable paste and gel also can comprise excipient, for example animal and plant fat, oil, wax, paraffin, starch, Tragacanth, cellulose derivative, Polyethylene Glycol, silicone, bentonite, silicic acid, Pulvis Talci, zinc oxide or their mixture.
Except that The compounds of this invention, powder and spray also can comprise excipient, for example the mixture of lactose, Pulvis Talci, silicic acid, aluminium hydroxide, calcium silicates, polyamide powder or these materials.Spray also can comprise propellant, for example chloro-fluoro-carbon kind usually.
Transdermal patch has the advantage that extra may command chemical compound is administered to health.Can or be formulated to this type of dosage form of preparation in the suitable medium with compound dissolution.Also can use absorption enhancer to improve the flux that chemical compound passes skin.Can control speed by rate controlling membranes being provided or chemical compound being distributed in polymeric matrix or the gel.
Antiviral activity
The amount of suppression of The compounds of this invention or dosage range can for about 0.01mg/Kg to about 500mg/Kg, perhaps about 1 to about 50mg/Kg.Amount of suppression or dosage also can change according to route of administration and with the common probability of using of other medicines.
The Therapeutic Method according to the present invention, the Therapeutic Method according to the present invention, by giving the The compounds of this invention of patient's anti-hepatitis c virus effective dose or amount of suppression, treatment or prevention patient's (for example people or low wait mammal) viral infection, and dosage and administration time length are that the required result of realization is necessary.Other method of the present invention is to handle biological sample with the amount of suppression of the chemical compound of the present composition, and dosage and administration time length are to realize that required result is necessary.
" the anti-hepatitis c virus effective dose " of term The compounds of this invention used herein is meant the chemical compound of q.s, make biological sample or patient's viral load reduction (for example produce viral load and be reduced at least 10%, preferably at least 50%, more preferably at least 80%, most preferably at least 90% or 95%).As medical domain was well-known, in any therapeutic treatment, the anti-hepatitis c virus effective dose of The compounds of this invention was to obtain the dosage of benefited/risk ratio rationally.
" amount of suppression " of term The compounds of this invention is meant that the amount that is enough to reduce hepatitis C virus carrying capacity among biological sample or the experimenter (for example produces viral load and is reduced at least 10%, preferably at least 50%, more preferably at least 80%, most preferably at least 90% or 95%).Should be appreciated that when the The compounds of this invention of described amount of suppression is applied to the experimenter it is the rational benefit/risk ratio that is applicable to the determined any treatment of doctor.Term used herein " biological sample " is meant the material of the biogenetic derivation that is intended to be applied to the experimenter.The example of biological sample includes, but are not limited to subgroup of blood and component such as blood plasma thereof, platelet, hemocyte or the like; Organ such as kidney, liver, heart, lung or the like; Sperm and ovum; Bone marrow and component thereof; Or stem cell.Therefore, another embodiment of the present invention is by described biological sample is contacted the method for handling biological sample with the chemical compound of the present invention or the pharmaceutical composition of amount of suppression.
After improving patient's the state of an illness, if desired, can give The compounds of this invention, compositions or the combination medicine of maintenance dose.Subsequently, dosage or frequency can be used as the function of symptom and reduce, and perhaps the both reduces, and up to keeping the dosage level that the state of an illness is improved, to desired level, should stop treatment in remission.But in case disease symptoms has any recurrence, the patient may need to carry out for a long time the intermittence treatment.
But, should be understood that total daily dose of The compounds of this invention and compositions will reasonably determined in the medical judgment scope by the attending doctor.Concrete inhibition dosage to any particular patient will depend on multiple factor, comprise the disease of being treated, the order of severity of disease; The activity of the particular compound of using; The concrete compositions of using; Patient's age, body weight, general health situation, sex and diet; The discharge rate of administration time, route of administration and the particular compound of using; The time that treatment continues; With associating of used particular compound or the medicine that uses simultaneously; And the known similar factor of medical domain.
Suppressed dosage in total day of The compounds of this invention and give the patient, suppressed dosage and be for example 0.01 to 50mg/kg body weight, 0.1 to 25mg/kg body weight more commonly used in total day with single agent or multi-agent.Unit-dose composition can comprise such dosage or its approximate number dosage is to constitute daily dose.Usually, therapeutic scheme of the present invention comprises that the about 10mg of the patient who needs this treatment is to about 1000mg The compounds of this invention/sky, with single agent or multi-agent administration.
Unless otherwise defined, the implication of all technology used herein and scientific terminology is consistent with the common implication of understanding of those of ordinary skill in the art.All publications mentioned in this article, patent, disclosed patent application and their list of references are incorporated this paper into by reference with its full content.
Abbreviation
In the explanation of scheme and embodiment, use following abbreviation:
ACN is an acetonitrile;
BME is a 2 mercapto ethanol;
BOP is benzotriazole-1-base oxygen base-three (dimethylamino) phosphorus
Figure BPA00001188361900931
Hexafluorophosphate;
COD is a cyclo-octadiene;
DAST is the diethylamino sulfur trifluoride;
DABCYL is 6-(N-4 '-carboxyl-4-(dimethylamino) diphenyl diimide)-amino hexyl-1-O-(2-cyano ethyl)-(N, N-diisopropyl)-phosphoramidite;
DCM is a dichloromethane;
DIAD is a diisopropyl azodiformate;
DIBAL-H is a diisobutyl aluminium hydride;
DIEA is a diisopropylethylamine;
DMAP is N, the N-dimethyl aminopyridine;
DME is a glycol dimethyl ether;
DMEM is DulbeccoShi improvement Eagles culture medium (Dulbecco ' s ModifiedEagles Media);
DMF is N, dinethylformamide;
DMSO is a dimethyl sulfoxine;
DUPHOS is
EDANS is 5-(2-amino-ethyl amino)-naphthalene-1-sulfonic acid;
EDCI or EDC are 1-(3-diethylamino propyl group)-3-ethyl-carbodiimide hydrochloride;
EtOAc is an ethyl acetate;
HATU is O (7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea
Figure BPA00001188361900933
Hexafluorophosphate;
Hoveyda ' s Cat. is dichloro (o-isopropoxy benzene methylene) (tricyclohexyl phosphine) ruthenium (II);
KHMDS is two (trimethyl silyl) potassamides;
Ms is a mesyl;
NMM is the N-4-methyl morpholine;
PyBrOP is bromo-three-pyrrolidinyl-phosphorus
Figure BPA00001188361900941
Hexafluorophosphate;
Ph is a phenyl;
RCM is the closed loop displacement reaction;
RT is a reverse transcription;
RT-PCR is a RT-polymerase chain reaction;
TEA is a triethylamine;
TFA is a trifluoroacetic acid;
THF is an oxolane;
TLC is a thin layer chromatography;
TPP or PPh 3Be triphenyl phasphine;
TBOC or Boc are tert-butoxycarbonyl; With
Xantphos is 4,5-pair-diphenylphosphino-9, and 9-dimethyl-9H-xanthene.
Synthetic method
Will be better understood Compounds and methods for of the present invention in conjunction with following synthetic schemes, these schemes have been described and can have been prepared the method for The compounds of this invention by it, and they only are used to the present invention is described and the unrestricted scope of the invention.The various distortion of disclosed embodiment and modification are obvious to those skilled in the art, and can comprise (without limitation) and chemical constitution of the present invention, substituent group, deutero-and/or method is relevant those this type of distortion and modification, and can not break away from the scope of spirit of the present invention and claims.
Scheme 1
Figure BPA00001188361900951
The general synthesis strategy of The compounds of this invention is shown in scheme 1.Make difluoromethyl P1 amino-acid compound 1-1 with the P2-P3 intermediate 1-2 couplings obtain ester 1-3, make its hydrolysis, obtain carboxylic acid 1-4.Acid 1-4 to sulfimine compound 1-5 conversion is to use CDI and sulfonamide RSO 2NH 2Realize.Final chemical compound 1-5 also is by the P2-P3 intermediate 1-2 with difluoromethyl P1 sulfimine compound 1-6 direct coupling preparation.Difluoromethyl P1 derivant and P2-P3 intermediate synthetic is described in following scheme.
Scheme 2
Figure BPA00001188361900952
Difluoromethyl P1 ( 1-1) the synthetic scheme 2 of listing in.List-Boc amino-acid ester further protection is two-Boc amino-acid ester 2-2.Chemical compound 2-2 oxicracking produces aldehyde 2-3, use for example diethylamino sulfur trifluoride (DAST) of amino sulfur trifluoride derivant then, make this aldehyde 2-3 change into difluoromethyl compound 2-4.Use HCl, 2-4 deprotections obtain the difluoromethyl P1 chemical compound of needs 1-1.
Scheme 3
Figure BPA00001188361900961
Difluoromethyl P1 sulfimide derivant 1-6 preparations shown in scheme 3.Chemical compound 2-4 hydrolysis obtain acid 3-1, use CDI/RSO 2NH 2/ DBU or HATU/DIPEA/RSO 2NH 2Make this acid 3-1 changes into 3-2. 3-2 deprotections obtain the intermediate of needs 1-6.
Scheme 4
The preparation intermediate 1-2 conventional method is illustrated in scheme 4.Non-annularity dipeptides precursor 4The-3rd, from the Boc-L-Terleu 4-1 and cis-L-hydroxyproline methyl ester 4-2 preparations.Chemical compound under the Mitsunobu condition 4-3 obtain chemical compound with the coupling of nucleophilic reagent W 4-5.Referring to O.Mitsunobu, Synthesis 1981,1-28 about the further details of Mitsunobu reaction for thing; D.L.Hughes, Org.React.29,1-162 (1983); D.L.Hughes, OrganicPreparations and Procedures Int.28,127-164 (1996); And J.A.Dodge, S.A.Jones, Recent Res.Dev.Org.Chem.1,273-283 (1997).Perhaps, chemical compound 4-3 react in the presence of alkali (for example triethylamine) with MsCl, obtain chemical compound 4-4.The MsO group is at alkali (Cs for example 2CO 3) there is the replacement of passing through nucleophilic reagent W down, obtain chemical compound 4-5.Then from chemical compound 4Remove acid protecting group in-5 and obtain formula 1-2 chemical compounds.The alternative methods of some synthesis step is described in U.S. Patent Application Serial Number 12/271,144, and its content is incorporated this paper into by reference with its integral body.
Scheme 5
The preparation intermediate 1Another universal method of-2 is illustrated in scheme 5.Non-annularity dipeptides precursor 5The-2nd, from the Boc-L-Terleu 4-1 and trans-L-1,2-hydroxyproline methyl ester 5-1 is synthetic.In the presence of alkali, reactant Q " and chemical compound 5-2 SN2 replaces, and obtains chemical compound 5-3.Perhaps, chemical compound 4-5 at first react with activator (for example CDI), then add reactant Q ', obtain chemical compound 4-5.Then from chemical compound 4-5 remove acid protecting group, obtain formula 1-2 chemical compounds.
All documents that this paper quotes, no matter be publication, electronic product, computer-readable medium for storing or other form, all clearly incorporate this paper by reference into its full content, described document includes but not limited to summary, paper, periodical, publication, file, paper, internet address, data base, patent and patent application.
Embodiment
With the following Examples, will understand The compounds of this invention and preparation method better, these embodiment are only as illustration purpose, rather than limitation of the scope of the invention.For those skilled in the art, the various changes and modifications of disclosed embodiment are conspicuous, and can carry out these type of changes and improvements (include but not limited to relevant with chemical constitution of the present invention, substituent group, derivant, preparation and/or method those) and can not break away from the scope of the present invention's spirit and claims.
Embodiment 1. Formula XI chemical compound, wherein
Figure BPA00001188361900982
Step 1A
Figure BPA00001188361900983
To the Boc-L-Terleu (4.544g, 19.65mmol), cis-L-hydroxyproline methyl ester (19.65mmol) and DIPEA (10.3ml, 59.1mmol) under 0 ℃, add in the solution in DMF (80ml) in batches HATU (7.84g, 20.6mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Residue obtains chemical compound 1a (7.8g) by silica gel chromatography purification (hexane/EtOAC=1: 1 to 1: 2).MS(ESI)：m/e359.24(M+H)。
Step 1B
Figure BPA00001188361900991
To above 1a (1.363g, 3.803mmol), 3-(thiophene-2-yl)-1H-quinoxaline-2-ketone (0.868g, 3.803mmol)) and triphenyl phasphine (2.0g, 7.6mmol) in the mixture in THF 0 ℃ drip down DIAD (1.5ml, 7.6mmol).Make the gained mixture place 15min. down, be warmed to room temperature then at 0 ℃.After 18 hours, this mixture is concentrated under vacuum, again residue is passed through chromatography purification (hexane/EtOAC=9: 1 to 7: 3), obtain 1b (1.8g).MS(ESI)：m/e 569.27(M+H)。
Step 1C
Figure BPA00001188361900992
(1.77g is 3.11mmol) at THF/MeOH/H to chemical compound 1b 2Add in the solution among the O (36ml-18ml-18ml) lithium hydroxide monohydrate (0.783g, 18.6mmol). this mixture was at room temperature stirred 20 hours.The most of organic solvent of vaporising under vacuum, again with the gained residue diluted with water, being acidified to pH again is 5 to 6.This mixture is extracted 3 times with EtOAc.Make the organic extract drying (MgSO of merging 4), filter, under vacuum, concentrate, obtain 1c (95%).MS(ESI)：m/e 555.26(M+H)。
Step 1D
Figure BPA00001188361901001
To chemical compound 1D-1 (6.6g, 25.85mmol) under-78 ℃, slowly add in the solution in THF (115ml) NaHMDS (1.0M, in THF, 28.5ml, 28.5mmol).Make this mixture after-78 ℃ are stirred 1 hour down, be added in the Boc2O (6.8g, 1.2 equivalents) among the THF (15ml) in being added in.The gained mixture is stirred, make temperature be elevated to ambient temperature overnight gradually again.Reactant mixture is diluted with EtOAc, with salt water washing (2x), dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 1D (8.05g).
Step 1E
Figure BPA00001188361901002
To chemical compound 1(0.5g 1.4mmol) adds NaIO in the solution in isopropyl alcohol (5ml) to d 4(0,9g 4.2mmol), then adds entry (5ml).In the mixture of this vigorous stirring, add OsO4 (0.4% aqueous solution, 0.22m, 2.5% equivalent).Make the gained mixture at room temperature stir 4h,, use NaHCO with the EtOAc dilution 3Aqueous solution, Na 2S 2O 3Aqueous solution, salt water washing, dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 1E (0.37g).
Step 1F
Figure BPA00001188361901011
To chemical compound 1E (2.9g, 8.1mmol) in the solution in dichloromethane (25ml)-78 ℃ add down diethylamino sulfur trifluorides (DAST) (2.7ml, 20.25mmol).The gained mixture was stirred 1 hour down at-78 ℃, experience 6h then to make temperature be elevated to room temperature gradually,, use NaHCO with the EtOAc dilution 3(2x), the salt water washing, dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 1F (1.49g).Reclaim initial substance 1f (1.2g).
Step 1G
Figure BPA00001188361901012
To chemical compound 1F (381mg, 1.4mmol) add in the solution in THF/MeOH (24ml-12ml) the lithium hydroxide monohydrate aqueous solution (1.0M, 12ml, 12mmol).This mixture was at room temperature stirred 2 days.The most of organic solvent of vaporising under vacuum, again with the gained residue diluted with water, being acidified to pH again is 5 to 6.This mixture is extracted 3 times with EtOAc.Make the organic extract drying (MgSO of merging 4), filter, under vacuum, concentrate, obtain chemical compound 1G (～100%) is directly used in next step.
Step 1H
Figure BPA00001188361901021
Make chemical compound 1(323mg 2.mmol) is dissolved in the 5ml dry DMF, gained solution is stirred 1 hour down at 40 ℃ again for g (1.33mmol) and carbonyl dimidazoles.With the cyclopropyl sulfonamide (483mg 4mmol) adds in the reactant mixture, then add DBU (0.26ml, 1.7mmol).Reactant mixture was stirred 18 hours down at 40 ℃.Reactant mixture is diluted reuse semi-saturation NaCl solution washing four times with ethyl acetate.With organic layer with anhydrous (MgSO 4) drying, under vacuum, concentrate again, obtain chemical compound 1H, it is directly used in next step.
Step 1I
Figure BPA00001188361901022
Make above chemical compound 1The solution of h in dichloromethane (1ml) is used in 1, and (4ml 16mmol) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain 1I is directly used in next step.
Step 1J
Figure BPA00001188361901023
To chemical compound 1C (0.075mmol), 1I (1 equivalent) and DIPEA (0.78ml, 0.448mmol) in the solution in DMF (3ml) 0 ℃ add down HATU (37mg, 0.097mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through the preparation HPLC purification, obtain title compound (10mg).MS(ESI)；m/z791.36(M+H)。
Embodiment 2. The chemical compound of formula XI, wherein
Figure BPA00001188361901031
Figure BPA00001188361901032
Figure BPA00001188361901033
Make the solution of chemical compound embodiment 1 (7mg) in dichloromethane (0.5ml) be used in 1, (1ml 4mmol) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain title compound (HCl salt).MS(ESI)：691.29(M+H)。
Embodiment 3. The chemical compound of formula XI, wherein
Figure BPA00001188361901034
Figure BPA00001188361901035
To chemical compound embodiment 2 (0.002mmol) and triethylamine (0.04ml, 35 equivalents) in the solution in DMF (1ml) 0 ℃ add down chloroformate cyclopentyl ester (1.5M, in toluene, 0.02ml, 0.03mmol).Make the gained mixture at room temperature stir 0.5 then to 2h, with the EtOAc dilution, with salt water washing (2x), dry (MgSO 4), under vacuum, concentrate again.Make residue pass through the preparation HPLC purification, obtain title compound (2mg).MS(ESI)；m/z 803.36(M+H)。
Embodiment 4. The chemical compound of formula XI, wherein
Figure BPA00001188361901042
And
To chemical compound 4-1 (2mg, 0.009mmol), chemical compound embodiment 2 (0.004mmol) and DIPEA (0.02ml, 0.12mmol) in the solution in DMF (1ml) 0 ℃ add down HATU (4mg, 0.01mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through the preparation HPLC purification, obtain title compound (2mg).MS(ESI)；m/z 88844(M+H)。
Embodiment 5. The chemical compound of formula XI, wherein A= , L=
Figure BPA00001188361901052
, Q= , And G=
Step 5A
To the Boc-L-Terleu (4.544g, 19.65mmol), trans-L-1,2-hydroxyproline methyl ester (19.65mmol) and DIPEA (10.3ml, 59.1mmol) under 0 ℃, add in the solution in DMF (80ml) in batches HATU (7.84g, 20.6mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Residue obtains chemical compound 5a (7.8g) by silica gel chromatography purification (hexane/EtOAC=1: 1 to 1: 2).MS(ESI)：m/e359.24(M+H)。
Step 5B
Figure BPA00001188361901056
To 5A (258mg, 0.72mmol) in the solution in DMF (5ml) 0 ℃ add down CDI (140mg, 0.86mmol).Make the gained mixture at room temperature stir 4, use chemical compound then 5b-1 (1mmol) handles.Make reactant mixture stir 4h down, be cooled to room temperature,, use KHSO with the EtOAc dilution at 60 ℃ 4(2x), saline (2x) washing.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through silica gel chromatography purification (hexane/EtOAC=2: 1 to 1: 1), obtain chemical compound 5b (142mg).MS(ESI)：m/e 522.33(M+H)。
Step 5C
Figure BPA00001188361901061
Chemical compound 5C is according to the described same operation method preparation of embodiment 1 step 1C.MS(ESI)：m/z 508.33(M+H)；514.34(M+Li)。
Step 5D
Figure BPA00001188361901062
Embodiment 5 is according to the described same operation method preparation of embodiment 1 step 1J.MS(ESI)：m/z 744.38(M+H)。
Embodiment 6. The chemical compound of formula XI, wherein
Figure BPA00001188361901071
And
Figure BPA00001188361901072
Title compound is to use embodiment 2 described same operation method preparations.MS(ESI)：m/z644.33(M+H)。
Embodiment 7. The chemical compound of formula XI, wherein
Figure BPA00001188361901073
And
Title compound is to use embodiment 3 described same operation method preparations.MS(ESI)：m/z756.45(M+H)。
Embodiment 8. The chemical compound of formula XI, wherein
Figure BPA00001188361901075
And
Figure BPA00001188361901076
Title compound is to use embodiment 4 described same operation method preparations.MS(ESI)：m/z841.55(M+H)。
Embodiment 9 to 74, and the formula XI chemical compound in the table 1 is according to embodiment 1 to 8 and the described maneuver preparation of synthetic method part.
Embodiment 75. Formula XII chemical compound, A=tert-butoxycarbonyl wherein, the L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is
Figure BPA00001188361901081
, and G=OH.
Step 75A
Figure BPA00001188361901082
To Boc cis-L-hydroxyproline methyl ester (2g, 8.15mmol) 75a-1 and Et3N (under 0 ℃, slowly add in 1.7ml, the 12.23mmol solution in dichloromethane MsCl (0.7ml, 8.96mmol).Make the gained mixture at room temperature stir 1～2h,, use the salt water washing, dry (MgSO with the EtOAc dilution 4), under vacuum, be concentrated into drying again, obtain rough 75a, it is directly used in next step.
Step 75B
Figure BPA00001188361901083
With above rough 75A, 9H-fluorenes-9-ketoxime (1.8g, 8.97mmol), cesium carbonate (4g, 12.2mmol) and the mixture of DMF (12ml) stir down 20h at 50 ℃, with the EtOAc dilution, use the salt water washing, drying (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=9: 1 to 4: 1), obtain 75B (2.736g).MS(ESI)：m/z323.11(M-Boc)；423.15(M+H)。
Step 75C
Figure BPA00001188361901091
With chemical compound 75B (960mg, 2.2mmol) solution in dichloromethane (3ml) is used in 1, and (5ml 20mmoL) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain 75C (～100%).
Step 75D
Figure BPA00001188361901092
To 75c(2.2mmol), the Boc-L-Terleu (560mg, 2.42mmol) and DIPEA (1.15ml, 6.6mmolmmol) in the solution in DMF (10ml) 0 ℃ add down HATU (920mg, 2.42mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make this residue by silicagel column purification (hexane/EtOAc=4: 1 to 2: 1), obtain chemical compound 75d (1.16g).MS(ESI)：m/z 536.23(M+H)。
Step 75E
To chemical compound 75D (1.06g, 1.98mmol) add in the solution in THF/MeOH/ water (20ml-10ml-10ml) lithium hydroxide monohydrate (494mg, 11.78mmol).This mixture was at room temperature stirred 18 hours.The most of organic solvent of vaporising under vacuum, again with the gained residue diluted with water, being acidified to pH again is 5 to 6.This mixture is extracted 3 times with EtOAc.Make the organic extract drying (MgSO of merging 4), filter, under vacuum, concentrate, obtain 75E (～100%).MS(ESI)：m/z 528.32(M+Li)。
Step 75F
Figure BPA00001188361901101
To chemical compound 75F-1 (6.6g, 25.85mmol) under-78 ℃, slowly add in the solution in THF (115ml) NaHMDS (1.0M, in THF, 28.5ml, 28.5mmol).Make this mixture after-78 ℃ are stirred 1 hour down, be added in the Boc2O (6.8g, 1.2 equivalents) among the THF (15ml).The gained mixture is stirred, make temperature be elevated to ambient temperature overnight gradually again.Reactant mixture is diluted with EtOAc, with salt water washing (2x), dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 75F (8.05g).
Step 75G
Figure BPA00001188361901102
To chemical compound 75(0.5g, (0,9g 4.2mmol), then adds entry (5ml) to f 1.4mmol) to add NaIO4 in the solution in isopropyl alcohol (5ml).In the mixture of this vigorous stirring, add OsO4 (0.4% aqueous solution, 0.22m, 2.5% equivalent).Make the gained mixture at room temperature stir 4h,, use NaHCO with the EtOAc dilution 3Aqueous solution, Na 2S 2O 3Aqueous solution, salt water washing, dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 75G (0.37g).
Step 75H
Figure BPA00001188361901111
To chemical compound 75G (2.9g, 8.1mmol) in the solution in dichloromethane (25ml)-78 ℃ add down diethylamino sulfur trifluorides (DAST) (2.7ml, 20.25mmol).The gained mixture was stirred 1 hour down at-78 ℃, experience 6h then to make temperature be elevated to room temperature gradually,, use NaHCO with the EtOAc dilution 3(2x), the salt water washing, dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 75H (1.49g).Reclaim initial substance 75g (1.2g).
Step 75I
With chemical compound 75H (491mg, 1.29mmol) solution in dichloromethane (1ml) is used in 1, and (6ml 24mmoL) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain 75I (～100%).
Step 75J
To 75i(129mmol), chemical compound 1e (657mg, 1.26mmol) and in the solution of DIPEA (0.7ml, 3 equivalents) in DMF (6ml) 0 ℃ add down HATU (540mg, 1.42mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make this residue by silicagel column purification (hexane/EtOAc=8: 2 to 6: 4), obtain chemical compound 75j (790mg).MS(ESI)：m/z 683.17(M+H)。
Step 75K
Figure BPA00001188361901122
To chemical compound 75J (770mg, 1.12mmol) add in the solution in THF/MeOH (20ml-10ml) the lithium hydroxide monohydrate aqueous solution (1.0M, 10ml, 10mmol).This mixture was at room temperature stirred 18 hours.The most of organic solvent of vaporising under vacuum, again with the gained residue diluted with water, being acidified to pH again is 5 to 6.This mixture is extracted 3 times with EtOAc.Make the organic extract drying (MgSO of merging 4), filter, under vacuum, concentrate, obtain title compound (～100%).MS(ESI)：m/z 655.15(M+H)；661.15(M+Li)。
Embodiment 76. Formula XII chemical compound, A=tert-butoxycarbonyl wherein, the L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is
Figure BPA00001188361901131
And
Figure BPA00001188361901132
Method I
Step 76A
Figure BPA00001188361901133
To chemical compound 75H (381mg, 1.4mmol) add in the solution in THF/MeOH (24ml-12ml) the lithium hydroxide monohydrate aqueous solution (1.0M, 12ml, 12mmol).This mixture was at room temperature stirred 2 days.The most of organic solvent of vaporising under vacuum, again with the gained residue diluted with water, being acidified to pH again is 5 to 6.This mixture is extracted 3 times with EtOAc.Make the organic extract drying (MgSO of merging 4), filter, under vacuum, concentrate, obtain chemical compound 76A (～100%) is directly used in next step.
Step 76B
Figure BPA00001188361901134
Make chemical compound 76(323mg 2.mmol) is dissolved in the 5ml dry DMF, gained solution is stirred 1 hour down at 40 ℃ again for a (1.33mmol) and carbonyl dimidazoles.With the cyclopropyl sulfonamide (483mg 4mmol) adds in the reactant mixture, then add DBU (0.26ml, 1.7mmol).Reactant mixture was stirred 18 hours down at 40 ℃.Reactant mixture is diluted reuse semi-saturation NaCl solution washing four times with ethyl acetate.With organic layer with anhydrous (MgSO 4) drying, under vacuum, concentrate again, obtain chemical compound 76B, it is directly used in following step 2C.
Perhaps, chemical compound 76B is to use coupling reagent HATU/ alkali and cyclopropyl sulfonamide from chemical compound 76The a preparation.
Step 76C
Figure BPA00001188361901141
Make above chemical compound 76The solution of h in dichloromethane (1ml) is used in 1, and (4ml 16mmol) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain 76C is directly used in next step.
Step 76D
Figure BPA00001188361901142
To chemical compound 75E (52mg, 0.1mmol) 76C (1 equivalent) and DIPEA (0.18ml, 1mmol) in the solution in DMF (2.5ml) 0 ℃ add down HATU (50mg, 0.13mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through the preparation HPLC purification, obtain title compound (40mg).MS(ESI)；m/z 758.28(M+H)。
Method II
Make chemical compound embodiment 75 (697mg, 1.06mmol) and carbonyl dimidazoles (343mg 2.1mmol) is dissolved in the 10ml dry DMF, gained solution is stirred 1 hour down at 40 ℃ again.With the cyclopropyl sulfonamide (385mg 3.18mmol) adds in the reaction, then add DBU (0.24ml, 1.6mmol).Reactant mixture stirred 2 hours down at 40 ℃.Reactant mixture is diluted reuse semi-saturation NaCl solution washing three times with ethyl acetate.With organic layer with anhydrous (MgSO 4) drying, concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 1 to 0: 1), obtain title compound (750mg).MS(ESI)；m/z 758.28(M+H)。
Embodiment 77. Formula XII chemical compound, A=H wherein, the L=tert-butyl group, R 1 And R 2 Connect with them The carbon atom that connects is together
Figure BPA00001188361901152
, and
Figure BPA00001188361901153
Figure BPA00001188361901154
The solution of chemical compound embodiment 76 (25mg) in dichloromethane (0.25ml) is used in 1, and (1ml 4mmol) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain title compound (HCl salt).MS(ESI)：658.21(M+H)。
Embodiment 78. Formula XII chemical compound, A=cyclopentyloxy carbonyl wherein, the L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is , and
Figure BPA00001188361901162
Figure BPA00001188361901163
To chemical compound embodiment 77 (0.014mmol) and triethylamine (0.08ml, 40 equivalents) in the solution in dichloromethane (1.5ml) 0 ℃ add down chloroformate cyclopentyl ester (1.5M, in toluene, 0.09ml, 0.135mmol).Make the gained mixture at room temperature stir 0.5 then to 2h, with the EtOAc dilution, with salt water washing (2x), dry (MgSO 4), under vacuum, concentrate again.Make residue pass through the preparation HPLC purification, obtain title compound (4mg).MS(ESI)；m/z 770.64(M+H)。
Embodiment 79. Formula XII chemical compound, A=cyclobutyl oxygen base carbonyl wherein, the L=tert-butyl group, R 1 And R 2 With them The carbon atom that connects is together
Figure BPA00001188361901164
, and
Title compound is to use embodiment 78 described same operation method preparations.MS(ESI)：m/z 756.27(M+H)。
Embodiment 80. Formula XII chemical compound, A=isopropyl oxygen base carbonyl wherein, the L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is
Figure BPA00001188361901171
, and
Figure BPA00001188361901172
Title compound is to use embodiment 78 described same operation method preparations.MS(ESI)：m/z 744.16(M+H)。
Embodiment 81. Formula XII chemical compound, A=ethoxy carbonyl wherein, the L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is , and
Figure BPA00001188361901174
Title compound is to use embodiment 78 described same operation method preparations.MS(ESI)：m/z 730.24(M+H)。
Embodiment 82. Formula XII chemical compound, A=methoxycarbonyl wherein, the L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is
Figure BPA00001188361901175
, and
Figure BPA00001188361901176
Title compound is to use embodiment 78 described same operation method preparations.MS(ESI)：m/z 716.25(M+H)。
Embodiment 83. Formula XII chemical compound, wherein The L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is
Figure BPA00001188361901178
, and
Figure BPA00001188361901179
Figure BPA00001188361901181
To chemical compound 9-1 (5.5mg, 0.025mmol), chemical compound embodiment 77 (0.013mmol) and DIPEA (0.22ml, 0.25mmol) in the solution in DMF (1ml) 0 ℃ add down HATU (10mg, 0.025mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through the preparation HPLC purification, obtain title compound (8mg).MS(ESI)；m/z 855.44(M+H)。
Embodiment 84. Formula XII chemical compound, wherein
Figure BPA00001188361901182
The L=tert-butyl group, R 1 And R 2 The carbon atom that connects with them is
Figure BPA00001188361901183
, and
Figure BPA00001188361901184
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 903.43(M+H)。
Embodiment 85. Formula XII chemical compound, wherein The L=tert-butyl group, R 1 And R 2 With it The carbon atom that connects be together , and
Figure BPA00001188361901187
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 768.57(M+H)。
Embodiment 86. Formula XII chemical compound, wherein
Figure BPA00001188361901191
The L=tert-butyl group, R 1 And R 2 With it The carbon atom that connects be together
Figure BPA00001188361901192
, and
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 767.20(M+H)。
Embodiment 87. Formula XII chemical compound, wherein
Figure BPA00001188361901194
The L=tert-butyl group, R 1 And R 2 With The carbon atom that they connect is together , and
Figure BPA00001188361901196
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 778.20(M+H)。
Embodiment 88. Formula XII chemical compound, wherein
Figure BPA00001188361901197
The L=tert-butyl group, R 1 And R 2 With it The carbon atom that connects be together
Figure BPA00001188361901198
, and
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 753.15(M+H)。
Embodiment 89. Formula XII chemical compound, wherein
Figure BPA000011883619011910
The L=tert-butyl group, R 1 And R 2 With it Connect Carbon atom is together
Figure BPA000011883619011911
, and
Figure BPA000011883619011912
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 769.13(M+H)。
Embodiment 90. Formula XII chemical compound, wherein
Figure BPA000011883619011913
The L=isopropyl, R 1 And R 2 With it The carbon atom that connects be together
Figure BPA00001188361901201
, And G=OH.
Title compound is to use embodiment 75 described same operation method preparations.MS(ESI)：m/z 647.43(M+Li)。
Embodiment 91. Formula XII chemical compound, wherein
Figure BPA00001188361901202
The L=isopropyl, R 1 And R 2 With it The carbon atom that connects be together
Figure BPA00001188361901203
, and
Figure BPA00001188361901204
Title compound is to use embodiment 76 described same operation method preparations.MS(ESI)：m/z 744.17(M+H)。
Embodiment 92. Formula XII chemical compound, wherein A=H , L=isopropyl, R 1 And R 2 Be connected with them Carbon atom be together
Figure BPA00001188361901205
, and
Figure BPA00001188361901206
Title compound is to use embodiment 77 described same operation method preparations.MS(ESI)：m/z 644.32(M+H)。
Embodiment 93. Formula XII chemical compound, wherein
Figure BPA00001188361901207
The L=isopropyl, R 1 And R 2 With it The carbon atom that connects be together , and
Figure BPA00001188361901209
Title compound is to use embodiment 78 described same operation method preparations.MS(ESI)：m/z 756.15(M+H)。
Embodiment 94. Formula XII chemical compound, wherein
Figure BPA000011883619012010
The L=isopropyl, R 1 And R 2 With it The carbon atom that connects be together
Figure BPA000011883619012011
, and
Figure BPA000011883619012012
Title compound is to use embodiment 78 described same operation method preparations.MS(ESI)：m/z 716.15(M+H)。
Embodiment 95. Formula XII chemical compound, wherein
Figure BPA00001188361901211
The L=isopropyl, R 1 And R 2 With The carbon atom that they connect is together
Figure BPA00001188361901212
, and
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 841.59(M+H)。
Embodiment 96. Formula XII chemical compound, wherein
Figure BPA00001188361901214
The L=isopropyl, R 1 And R 2 With it The carbon atom that connects be together , and
Figure BPA00001188361901216
Title compound is to use embodiment 83 described same operation method preparations.MS(ESI)：m/z 754.06(M+H)。
Embodiment 97 to 201, and table 2 Chinese style XII chemical compound is according to embodiment 75 to 96 and the described maneuver preparation of synthetic method part.
Embodiment 202 to 300, and table 3 Chinese style XIII chemical compound is according to embodiment 75 to 96 and the described maneuver preparation of synthetic method part.
Embodiment 301. Formula XIV chemical compound, wherein
Figure BPA00001188361901217
And
Figure BPA00001188361901218
Step 301A
Figure BPA00001188361901221
To the Boc-L-Terleu (4.544g, 19.65mmol), cis-L-hydroxyproline methyl ester (19.65mmol) and DIPEA (10.3ml, 59.1mmol) under 0 ℃, add in the solution in DMF (80ml) in batches HATU (7.84g, 20.6mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through silica gel chromatography purification (hexane/EtOAC=1: 1 to 1: 2), obtain chemical compound 301a (7.8g).MS(ESI)：m/e 359.24(M+H)。
Step 301B
Figure BPA00001188361901222
To chemical compound 301a(369mg, 1.02mmol) and Et 3Under 0 ℃, slowly add MsCl (0.12ml, 1.5 equivalents) in the solution of N (0.3ml, 2 equivalents) in dichloromethane (5ml).Make the gained mixture at room temperature stir 1～2h,, use the salt water washing, dry (MgSO with the EtOAc dilution 4), under vacuum, be concentrated into drying again, obtain rough 301b, it is directly used in next step.
Step 301C
Figure BPA00001188361901231
With chemical compound 301B, terazole derivatives 301c-1 (360mg, 2.04mmol), cesium carbonate (671g, 2.04mmol) and DMF (5ml) stir down 24h at 50 ℃, with the EtOAc dilution, use the salt water washing, drying (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=4: 1 to 2: 1), obtain 301C (88mg).MS(ESI)：m/z417.28(M-Boc)；517.36(M+H)。
Step 301D
Figure BPA00001188361901232
To chemical compound 301C (88mgg, 0.17mmol) add in the solution in THF/MeOH (5ml-2.5ml) Lithium hydrate (the 1M aqueous solution, 2.5ml).This mixture was at room temperature stirred 18 hours.The most of organic solvent of vaporising under vacuum, again with the gained residue diluted with water, being acidified to pH again is 5 to 6.This mixture is extracted 3 times with EtOAc.Make the organic extract drying (MgSO of merging 4), filter, under vacuum, concentrate, obtain 1D (～100%).MS(ESI)：m/z509.25(M+Li)。
Step 301E
To chemical compound 301E-1 (6.6g, 25.85mmol) under-78 ℃, slowly add in the solution in THF (115ml) NaHMDS (1.0M, in THF, 28.5ml, 28.5mmol).Make this mixture after-78 ℃ are stirred 1 hour down, be added in the Boc2O (6.8g, 1.2 equivalents) among the THF (15ml).The gained mixture is stirred, make temperature be elevated to ambient temperature overnight gradually again.Reactant mixture is diluted with EtOAc, with salt water washing (2x), dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 301E (8.05g).
Step 301F
To chemical compound 301(0.5g, (0,9g 4.2mmol), then adds entry (5ml) to e 1.4mmol) to add NaIO4 in the solution in isopropyl alcohol (5ml).In the mixture of this vigorous stirring, add OsO4 (0.4% aqueous solution, 0.22m, 2.5% equivalent).Make the gained mixture at room temperature stir 4h,, use NaHCO with the EtOAc dilution 3Aqueous solution, Na 2S 2O 3Aqueous solution, salt water washing, dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 301F (0.37g).
Step 301G
Figure BPA00001188361901251
To chemical compound 301F (2.9g, 8.1mmol) in the solution in dichloromethane (25ml)-78 ℃ add down diethylamino sulfur trifluorides (DAST) (2.7ml, 20.25mmol).The gained mixture was stirred 1 hour down at-78 ℃, experience 6h then to make temperature be elevated to room temperature gradually,, use NaHCO with the EtOAc dilution 3(2x), the salt water washing, dry (MgSO 4), concentrate in a vacuum again.Make residue pass through silica gel chromatography purification (hexane/EtOAc=1: 0 to 85: 15), obtain 1G (1.49g).Reclaim initial substance 301f (1.2g).
Step 301H
Figure BPA00001188361901252
To chemical compound 301G (381mg, 1.4mmol) add in the solution in THF/MeOH (24ml-12ml) the lithium hydroxide monohydrate aqueous solution (1.0M, 12ml, 12mmol).This mixture was at room temperature stirred 2 days.The most of organic solvent of vaporising under vacuum, again with the gained residue diluted with water, being acidified to pH again is 5 to 6.This mixture is extracted 3 times with EtOAc.Make the organic extract drying (MgSO of merging 4), filter, under vacuum, concentrate, obtain chemical compound 301h(～100%) is directly used in next step.
Step 301I
Figure BPA00001188361901261
Make chemical compound 301(323mg 2.mmol) is dissolved in the 5ml dry DMF, gained solution is stirred 1 hour down at 40 ℃ again for h (1.33mmol) and carbonyl dimidazoles.With the cyclopropyl sulfonamide (483mg 4mmol) adds in the reactant mixture, then add DBU (0.26ml, 1.7mmol).Reactant mixture was stirred 18 hours down at 40 ℃.Reactant mixture is diluted reuse semi-saturation NaCl solution washing four times with ethyl acetate.With organic layer with anhydrous (MgSO 4) drying, under vacuum, concentrate again, obtain chemical compound 301I, it is directly used in next step.
Step 301J
With above chemical compound 301The solution of i in dichloromethane (1ml) is used in 1, and (4ml 16mmol) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain 301J is directly used in next step.
Step 301K
To chemical compound 301D (0.075mmol), 301In j (1 equivalent) and DIPEA (0.65ml, the 5 equivalents) solution in DMF (2ml) 0 ℃ add down HATU (47mg, 0.12mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through the preparation HPLC purification, obtain title compound (17mg).MS(ESI)；m/z739.41(M+H)。
Embodiment 302. Formula XIV chemical compound, wherein
Figure BPA00001188361901271
And
Make the solution of chemical compound embodiment 301 (10mg) in dichloromethane (0.5ml) be used in 1, (1ml 4mmol) handles the 4N HCl in the 4-dioxane.This mixture was at room temperature stirred 1 hour, be concentrated into drying, obtain title compound (HCl salt).MS(ESI)：639.32(M+H)。
Embodiment 303. Formula XIV chemical compound, wherein
Figure BPA00001188361901274
With And
Figure BPA00001188361901275
Figure BPA00001188361901281
To embodiment 302 chemical compounds (0.008mmol) and triethylamine (0.04ml, 35 equivalents) in the solution in DMF (1ml) 0 ℃ add down chloroformate cyclopentyl ester (1.5M, in toluene, 0.03ml, 0.045mmol).Make the gained mixture at room temperature stir 0.5 then to 2h, with the EtOAc dilution, with salt water washing (2x), dry (MgSO 4), under vacuum, concentrate again.Make residue pass through the preparation HPLC purification, obtain title compound (2mg).MS(ESI)；m/z 751.49(M+H)。
Embodiment 304. Formula XIV chemical compound, wherein
Figure BPA00001188361901282
And
Figure BPA00001188361901283
To chemical compound 4-1 (8mg, 0.038mmol), chemical compound embodiment 302 (0.008mmol) and DIPEA (0.04ml, 0.23mmol) in the solution in DMF (1ml) 0 ℃ add down HATU (16mg, 0.042mmol).This mixture is at room temperature stirred 18h, with EtOAc dilution, reuse semi-saturation NaCl solution washing four times.With the anhydrous MgSO of organic facies 4Drying is filtered, and concentrates under vacuum then.Make residue pass through the preparation HPLC purification, obtain title compound (2mg).MS(ESI)；m/z 8836.47(M+H)。
Embodiment 305 to 499: the formula VIII chemical compound in the table 4 is according to embodiment 301 to 304 described maneuver preparations.
The compounds of this invention demonstrates effective inhibition activity to HCV NS3 protease.The analytic process that following examples are described wherein can be at anti-HCV effect test The compounds of this invention.
Embodiment 500.NS3/NS4a protease activity determination
Utilize the internal quenched fluorogenic substrate to measure HCV protease activities and inhibitory action.DABCYL and EDANS group are connected in the opposite ends of small peptide.Proteolytic cleavage has been alleviated the cancellation of DABCYL group to EDANS fluorescence.Utilize the excitation wavelength of 355nm and the emission wavelength of 485nm to measure fluorescence by Molecular Devices Fluoromax (or equivalent).
In Coming white half regional 96-orifice plate (VWR 29444-312[Corning 3693]), measure total length NS3HCV protease 1b (final enzyme concentration 1 arrives 15nM) with the constraint of NS4A cofactor.Measuring buffer supplies with 10 μ M NS4A cofactor Pep 4A (Anaspec 25336 or self, MW 1424.8).RET S1 (Ac-Asp-Glu-Asp (EDANS)-Glu-Glu-Abu-[COO] Ala-Ser-Lys-(DABCYL)-NH 2(SEQ ID NO:4) ..AnaSpec 22991, MW 1548.6) as the fluorescence peptide substrates.Measure 50mM Hepes, 30mM NaCl and 10mM BME that buffer contains pH 7.5.At room temperature, under the condition that does not have and exist inhibitor, enzyme reaction was carried out 30 minutes.
(Anaspec 25345 for inhibitor peptides HCV Inh 1, MW 796.8) Ac-Asp-Glu-Met-Glu-Glu-Cys-OH, (Anaspec 25346 for (SEQ ID NO:5) [20 ℃] and HCV Inh 2, MW 913.1) Ac-Asp-Glu-Dif-Cha-Cys-OH, (SEQ ID NO:6) is as reference compound.
The IC50 value is utilized to establish an equation down and 205 is utilized XLFit calculating: y=A+ ((B-A)/(1+ ((C/x) ^D))) in ActivityBase (IDBS).
Embodiment 501-measures based on the replicon of cell
Use Huh 11-7 to finish the quantitative analysis (Lohmann, et al Science 285:110-113,1999) of replicon rna (based on the mensuration of HCV cell).Make cell with 4x10 3The cells/well bed board is on 96 orifice plates and contain the culture medium of DMEM (high glucose), 10% hyclone, penicillin-streptomycin and non essential amino acid.37 ℃ of incubations of cell are at 7.5%CO 2In the calorstat.When incubation period finishes, utilize Ambion RNAqueous 96 test kits (catalog number AM1812) by extracting and the total RNA of purification in the cell.For the amplification HCV RNA so that can pass through the enough materials of HCV specific probe (following) detection, the reverse transcription of HCV Auele Specific Primer (following) mediation HCV RNA and the amplification that utilizes the cDNA that TaqMan one one step RT-PCR Master Mix test kit (Applied Biosystems, catalog number (Cat.No.) 4309169) undertakies by polymerase chain reaction (PCR).The nucleotide sequence of RT-PCR primer, it is positioned at the genomic NS5B of HCV zone, and is as follows:
HCV forward primer " RBNS5bfor "
5’GCTGCGGCCTGTCGAGCT (SEQ ID NO：1)：
HCV reverse primer " RBNS5Brev "
5’CAAGGTCGTCTCCGCATAC(SEQ ID NO 2)。
Utilize Applied Biosystems (ABI) Prism 7500 sequence detection systems (SDS) to finish the detection of RT-PCR product, described system detects and makes the time spent emitting fluorescence with the probe of fluorescence reporter molecule dyestuff and quencher dye marker in the PCR course of reaction.In each PCR cyclic process, measure the increase of fluorescence volume and the recruitment of reflection RT-PCR product.Particularly, quantitative analysis is based on threshold cycle, and wherein amplification is drawn and intersected the fluorescence threshold of a qualification.Sample threshold cycle and known standard the highly sensitive mensuration (ABI User Bulletin#2, on December 11st, 1997) of template concentrations relatively relatively is provided in the different samples.Utilize ABI SDS program 1.7 analysis of version data.By utilizing the HCV RNA standard and the standard curve of known copy number relative template concentrations can be changed into RNA copy number (ABI User Bulletin#2, on December 11st, 1997).
Utilize the probe in detecting RT-PCR product of following labelling:
5’FAM-CGAAGCTCCAGGACTGCACGATGCT-TAMRA(SEQID NO：3)
FAM=fluorescence reporter molecule dyestuff.
TAMRA:=quencher dyestuff.
RT is reflected at 48 ℃ to carry out 30 minutes, carried out PCR then.The thermal cycler parameter that is used for the PCR reaction on ABI Prism 7500 sequence detection systems is: 95 ℃ of 1 circulations in 10 minutes, 40 circulations respectively are included in 95 ℃ of incubations of 15 seconds and 60 ℃ of second incubations of 1 minute then.
In order to proofread and correct the data of internal contrast molecule and cell RNA, pair cell messenger RNA glyceraldehyde-3-phosphate dehydrogenase (GAPDH) carries out RT-PCR.The GAPDH copy number is highly stable in used cell line.Identical RNA sample to its HCV copy number to be determined carries out GAPDHRT-PCR.GAPDH primer and probe are included in the ABI Pre-Developed TaqMan detection kit (catalog number 4310884E).The ratio of HCV/GAPDH RNA is used to calculate the activity in order to the chemical compound of estimating the inhibition of HCV rna replicon.
Chemical compound as HCV replication inhibitors (based on the mensuration of cell) is comprising the Huh-7 cell Activity in the replicon of system
By in the cell that relatively is exposed to chemical compound with the cell that is exposed to DMSO solvent (negative control) in correction in the amount of the HCV of GAPDH (for example, the ratio of HCV/GAPDH) RNA measure specificity anti--virus compound to the Huh-11-7 cell in the effect of HCV replicon rna level.Particularly, cell is with 4x10 3The cells/well bed board in 96 orifice plates and with one of following substances incubation: 1) contain the culture medium of 1%DMSO (0% suppress contrast), perhaps 2) contain the culture medium/1%DMSO of fixed concentration chemical compound.Then as mentioned above with 96 orifice plates at 37 ℃ of incubations 4 days (EC50 mensuration).Suppressing percentage ratio is defined as:
% inhibition=100-100*S/C1
Wherein
The ratio of HCV RNA copy number in the S=sample/GAPDH RNA copy number;
C1=0% suppresses the contrast (ratio of HCV RNA copy number/GAPDH RNA copy number in the culture medium/1%DMSO).
Begin and finish three log chemical compounds of series, three times of dilutions are added into the dose-effect curve that produces inhibitor in the hole by specific compound with minimum 0.23nM concentration with maximum concentration 1.5uM.If the IC50 value not in the range of linearity of curve, is then carried out further serial dilution (for example 500nM to 0.08nM).With IDBS Activity Base program " XL Fit ", use 4-parameter, nonlinear regression and fitting (model #205, edition 4 .2.1, structure 16) to measure EC50.

Claims (23)

1. formula (I) chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Figure FPA00001188361800011
Wherein
M does not exist or is selected from O, S, S (O), SO 2, NH, O (CO), NH (CO), NH (CO) NH, NHSO 2, NHSO 2The alkenylene of alkylidene, alkenylene or the replacement of NH, NH (CO) O, alkylidene, replacement;
Cy is selected from aryl, the heteroaryl of hydrogen, aryl, replacement; The cycloalkenyl group of the cycloalkyl of the heterocycle of the heteroaryl that replaces, heterocycle, replacement, cycloalkyl, replacement, cycloalkenyl group, replacement and
Figure FPA00001188361800012
Wherein
R 1And R 2Be independently selected from:
A) hydrogen;
B) aryl;
C) aryl of Qu Daiing;
D) heteroaryl;
E) heteroaryl of Qu Daiing;
F) heterocycle of heterocycle or replacement;
G)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
H) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
I)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
J) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group;
K)-Q-R 3, wherein Q is (CO), (CO) O, (CO) NR 4, (SO), (SO 2), (SO 2) NR 4And R 3And R 4Be independently selected from:
(i) hydrogen;
(ii) aryl;
The (iii) aryl of Qu Daiing;
(iv) heteroaryl;
(the v) heteroaryl of Qu Daiing;
(vi) heterocycle;
(the vii) heterocycle of Qu Daiing;
(viii)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(ix) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(x)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
(xi) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group; Perhaps R 1And R 2The carbon atom that connects with their forms and is selected from following loop section: replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle; Perhaps replace or unsubstituted cycloalkyl, cycloalkenyl group or heterocycle its comprise that with one or more following group condenses: the cycloalkenyl group of the cycloalkyl of the heterocycle of the heteroaryl of the aryl of aryl, replacement, heteroaryl, replacement, heterocycle, replacement, cycloalkyl, replacement, cycloalkenyl group and replacement separately;
G is-E-R 3, wherein E does not exist or E is O, CO, (CO) O, (CO) NH, NR 5, NH (CO), NH (CO) NH, NH (SO 2) NH or NHSO 2
A is selected from R 5, (CO) R 5, (CO) OR 5, (CO) NHR 5, SO 2R 5, (SO 2) OR 5And SO 2NHR 5
R 5Be selected from:
A) hydrogen
B) aryl;
C) aryl of Qu Daiing;
D) heteroaryl;
E) heteroaryl of Qu Daiing;
F) heterocycle;
G) heterocycle of Qu Daiing;
H)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
I) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
J)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
K) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group;
B is H or CH 3
L is selected from:
(xii) hydrogen;
(xiii) aryl;
(xiv) aryl of Qu Daiing;
(xv) heteroaryl;
(xvi) heteroaryl of Qu Daiing;
(xvii) heterocycle;
(xviii) heterocycle of Qu Daiing;
(xix)-C 1-C 8Alkyl ,-C 2-C 8Thiazolinyl or-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(xx) replace-C 1-C 8Alkyl, replacement-C 2-C 8Thiazolinyl or replacement-C 2-C 8Alkynyl contains 0,1,2 or 3 hetero atom that is selected from O, S or N separately;
(xxi)-C 3-C 12Cycloalkyl or-C 3-C 12Cycloalkenyl group;
(xxii) replace-C 3-C 12Cycloalkyl or replacement-C 3-C 12Cycloalkenyl group;
Z 1And Z 2Be independently selected from halogen;
M=0,1,2 or 3;
N=1,2 or 3; With
H=1,2 or 3.
2. the chemical compound of claim 1, wherein this chemical compound is formula II chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Wherein A, L, M, Cy, G, Z 1And Z 2It is the definition in the claim 1 as described above.
3. the chemical compound of claim 1, wherein this chemical compound is formula III chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Figure FPA00001188361800042
Wherein
R 6Be selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement; J be do not exist or be selected from-O-,-S-,-N (R 5)-,-C (O)-,-C (O) N (R 5)-,-C (O) O-,-N (R 5) C (O)-,-NH (CO) NH-,-N (R 5) SO 2-, alkylidene, alkenylene, alkynylene;
Each R 71, R 72, R 73And R 74Be independently selected from:
(i) hydrogen;
(ii) halogen;
(iii)-NO 2；
(iv)-CN；
(v)-M-R 4, wherein M does not exist, perhaps O, S, NH, N (R 5);
(vi) aryl;
(the vii) aryl of Qu Daiing;
(viii) heteroaryl;
(ix) heteroaryl of Qu Daiing;
(x) Heterocyclylalkyl; With
(xi) Heterocyclylalkyl of Qu Daiing;
Wherein A, L, G, Z 1, Z 2, R 4And R 5It is the definition in the claim 1 as described above.
4. the chemical compound of claim 1, wherein this chemical compound is formula IV chemical compound or the acceptable salt of its pharmacy, ester or prodrug::
Figure FPA00001188361800051
Wherein
R 6Be selected from the heteroaryl of aryl, heteroaryl and the replacement of aryl, replacement; J be do not exist or be selected from-O-,-S-,-N (R 5)-,-C (O)-,-C (O) N (R 5)-,-C (O) O-,-N (R 5) C (O)-,-NH (CO) NH-,-N (R 5) SO 2-, alkylidene, alkenylene, alkynylene; R wherein 5Be that first embodiment is defined.
Each R 71, R 72, R 73And R 74Be independently selected from:
(i) hydrogen;
(ii) halogen;
(iii)-NO 2；
(iv)-CN；
(v)-M-R 4, wherein M does not exist, perhaps O, S, NH, N (R 5);
(vi) aryl;
(the vii) aryl of Qu Daiing;
(viii) heteroaryl;
(ix) heteroaryl of Qu Daiing;
(x) Heterocyclylalkyl; With
(xi) Heterocyclylalkyl of Qu Daiing;
With A, L, G, Z 1Z 2, R 4And R 5It is the definition in the claim 1 as described above.
5. the chemical compound of claim 1, wherein this chemical compound is formula V chemical compound or the acceptable salt of its pharmacy, ester or prodrug:
Figure FPA00001188361800061
Each R wherein 71, R 72, R 73And R 74Be independently selected from:
(i) hydrogen;
(ii) halogen;
(iii)-NO 2；
(iv)-CN；
(v)-M-R 4, wherein M does not exist, perhaps O, S, NH, N (R 5);
(vi) aryl;
(the vii) aryl of Qu Daiing;
(viii) heteroaryl;
(ix) heteroaryl of Qu Daiing;
(x) Heterocyclylalkyl; With
(xi) Heterocyclylalkyl of Qu Daiing;
With A, L, G, Z 1And Z 2Be as the definition in the claim 1.
6. the chemical compound of claim 1, it is selected from formula XI chemical compound, and wherein A, L, Q and G are described in table 1:
Table 1
Figure FPA00001188361800072
Figure FPA00001188361800081
Figure FPA00001188361800101
Figure FPA00001188361800121
7. the chemical compound of claim 1, it is selected from formula XII chemical compound, wherein R 1And R 2The carbon that connects with them forms R 1R 2, and A, R 1R 2, L and G be described in Table 2In each embodiment:
Figure FPA00001188361800122
Table 2
Figure FPA00001188361800131
Figure FPA00001188361800141
Figure FPA00001188361800151
Figure FPA00001188361800161
Figure FPA00001188361800191
Figure FPA00001188361800201
Figure FPA00001188361800211
Figure FPA00001188361800221
8. the chemical compound of claim 1, it is by formula (XIII) expression,
Figure FPA00001188361800222
Wherein Rx, L, W 1With G is to be described in Table 3In each embodiment:
Table 3
Figure FPA00001188361800231
Figure FPA00001188361800241
Figure FPA00001188361800251
Figure FPA00001188361800271
Figure FPA00001188361800281
Figure FPA00001188361800301
Figure FPA00001188361800311
Figure FPA00001188361800321
9. the chemical compound of claim 1, it is represented by formula XIV,
Figure FPA00001188361800322
Wherein A, L, W 1With G is to be described in Table 4In each embodiment:
Table 4
Figure FPA00001188361800331
Figure FPA00001188361800341
Figure FPA00001188361800351
Figure FPA00001188361800371
Figure FPA00001188361800381
Figure FPA00001188361800391
Figure FPA00001188361800401
Figure FPA00001188361800411
Figure FPA00001188361800421
Figure FPA00001188361800431
Figure FPA00001188361800451
Figure FPA00001188361800461
Figure FPA00001188361800471
Figure FPA00001188361800481
Figure FPA00001188361800491
Figure FPA00001188361800501
Figure FPA00001188361800521
Figure FPA00001188361800531
Figure FPA00001188361800541
10. pharmaceutical composition, it comprises chemical compound or the acceptable salt of its pharmacy, ester or prodrug with the claim 1 of the amount of suppression of pharmaceutically acceptable carrier or excipient composition.
11. the method for treatment experimenter viral infection, this method comprises the pharmaceutical composition of using the claim 10 of amount of suppression to described experimenter.
12. the method for claim 11, wherein this viral infection is a hepatitis C virus.
13. suppress the method for hepatitis c viral replication, this method comprises the pharmaceutical composition that the claim 10 of amount of suppression is provided to hepatitis C virus NS protease.
14. the method for claim 11, it further comprises uses other anti--hepatitis C virus toxic agent simultaneously.
15. the method for claim 14, wherein said other anti--hepatitis C virus toxic agent is selected from alpha-interferon, beta-interferon, ribavirin and amantadine.
16. the method for claim 14, wherein state other anti--the hepatitis C virus toxic agent is the inhibitor of hepatitis C virus unwindase, polymerase, metalloproteases or IRES.
17. the pharmaceutical composition of claim 10, it further comprises another anti-HCV agent.
18. the pharmaceutical composition of claim 10, it further comprises and is selected from following medicine: interferon, ribavirin, amantadine, another HCV protease inhibitor, HCV AG14361, HCV unwindase inhibitor or internal ribosome entry site inhibitor.
19. the pharmaceutical composition of claim 10, it further comprises glycol interferon.
20. the pharmaceutical composition of claim 10, it further comprises another antiviral agent, antibacterial, antifungal or anticarcinogen, perhaps immunomodulator.
21. the compositions of claim 10, it further comprises Cytochrome P450 monooxygenase inhibitor or the acceptable salt of its pharmacy.
22. the compositions of claim 21, wherein said Cytochrome P450 monooxygenase inhibitor is a ritonavir.
23. give the method for the patient's co-administered that needs the anti-third type viral therapy, comprising Cytochrome P450 monooxygenase inhibitor or the acceptable salt of its pharmacy and described formula I chemical compound of claim 1 or the acceptable salt of its pharmacy.
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